Abstract
RNA helicases unwind their RNA substrates in an ATP-dependent reaction, and are central to all cellular processes involving RNA. They have important roles in viral life cycles, where RNA helicases are either virus-encoded or recruited from the host. Vertebrate RNA helicases sense viral infections, and trigger the innate antiviral immune response. RNA helicases have been implicated in protozoic, bacterial and fungal infections. They are also linked to neurological disorders, cancer, and aging processes.
Genome-wide studies continue to identify helicase genes that change their expression patterns after infection or disease outbreak, but the mechanism of RNA helicase action has been defined for only a few diseases. RNA helicases are prognostic and diagnostic markers and suitable drug targets, predominantly for antiviral and anti-cancer therapies. This review summarizes the current knowledge on RNA helicases in infection and disease, and their growing potential as drug targets.
1. Introduction: RNA helicases
RNA helicases catalyze the ATP-dependent unwinding of RNA duplexes, and structural rearrangements of RNAs and RNA-protein complexes (RNPs) in a large number of cellular processes. They accompany mRNAs from transcription through processing (splicing, editing), transport and translation to degradation, and are involved in the assembly of RNPs, such as the ribosome and the spliceosome. Due to their central role, malfunction often leads to disease. RNA helicases also play an important role in viral infection. RNA viruses either contain their own RNA helicases, or recruit cellular helicases from the host to support their lifecycle. On the other hand, RNA helicases sense foreign RNAs in vertebrates, and mediate the antiviral immune response.
Helicases have been grouped into different superfamilies, based on shared conserved motifs.1 The majority of RNA helicases belong to the DEAD and DExH box families within the superfamily 2 (SF2) of helicases, named after the sequence of a conserved motif. SF2 also comprises the RecQ and SWI/SNF families of DNA helicases. Members of the DEAD box and DExH box families share a similar three-dimensional core structure, comprised of two flexibly linked RecA domains. Within each family, specific conserved helicase signature motifs are located in a similar three-dimensional arrangement on the core structure (Fig. 1), where they contribute to ATP binding and hydrolysis, RNA binding, and RNA unwinding. In many cases, the core is flanked by N- and/or C-terminal extensions.
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01 June 2012Figure 1. DEAD and DExH box RNA helicases. (A) Scheme of DEAD and DExH box helicase core architecture and conserved motifs. The RNA helicase core consists of two globular domains (orange, blue) that carry conserved motifs Q (red, only present in DEAD box proteins), I, Ia, Ib, Ic, II, III, IV, Iva, V, and VI that mediate ATP binding and hydrolysis, RNA binding, and coupling of the nucleotide cycle to helicase activity. The * denotes that the Q-motif is specific for DEAD box proteins, but absent in DExH box proteins. The helicase core is often flanked by N- and C-terminal extensions (NTE, CTE). (B) Open and closed conformations of DEAD and DExH box proteins. The crystal structures of eIF4A-III (left, PDB-IDs 2HXY and 2HYI) and DENV NS3 helicase (right, PDB-IDs 2JLQ and 2JLV) in the open conformation in the absence of ligands (top), and in the closed conformation in the ternary complex with nucleotide (ADPNP) and RNA (bottom). The conserved motifs are depicted in space-filling representation in the same color code as in A, the bound RNA and ADPNP are depicted in dark yellow. In DEAD box proteins, the inter-domain cleft is wider than in DExH proteins, and the conformational change upon binding of ATP and RNA is larger. DEAD box proteins bind single stranded RNA in a bent form, whereas RNA bound to DExH box proteins is extended. (C) Model for the catalytic cycle of RNA unwinding in DEAD and DExH box proteins. Left: DEAD box proteins adopt an open conformation in the absence of ligands (1). Binding of RNA and ATP to DEAD box proteins causes the formation of a closed conformer, forming the active site for ATP hydrolysis and the bipartite RNA binding site. In this state, the bound RNA is distorted and locally destabilized (2). From an activated complex (3), the first RNA strand can dissociate. After ATP hydrolysis (4,5), phosphate release is coupled to a re-opening of the cleft in the helicase core, and the dissociation of the second RNA strand (5 to 6). Exchange of ADP for ATP starts a second catalytic cycle. Right: Mechanism of HCV-NS3-mediated RNA unwinding as a paradigm for RNA unwinding by DExH box proteins that translocate along one of the strands. In the nucleotide-free state (1), the two pincer residues (orange and blue triangles) contact the RNA backbone with a distance of three nucleotides. ATP binding leads to a closure o the helicase core, and a repositioning of the pincers that have come closer (2), thereby creating tension between the helicase core and domain 3. Upon ATP hydrolysis and product release, the helicase core re-opens, and the pincers move further apart again (3). Hydrolysis of one ATP has caused a translocation of the helicase core by one nucleotide. In a subsequent ATP hydrolysis cycle, the translocation is repeated (4,5), further increasing the tension between the core and domain 3. In a third ATP hydrolysis cycle (6,7), the advancement by a third nucleotide triggers the release of this tension (“spring-loaded” mechanism), leading to a burst of unwinding 3 base pairs (7). The N- and C-terminal domains of the helicase core (H1, H2) are depicted in orange and blue, the domain 3 of DExH proteins in yellow. ATP is shown in green. The DExH box protein pincer residues and Trp501 that has been implicated in the “spring-loaded” mechanism (see main text) are depicted as orange, blue and yellow triangles.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/krnb20/2012/krnb20.v009.i06/rna.20090/20141027/images/medium/krnb_a_10920090_f0001.gif"})
Figure 1. DEAD and DExH box RNA helicases. (A) Scheme of DEAD and DExH box helicase core architecture and conserved motifs. The RNA helicase core consists of two globular domains (orange, blue) that carry conserved motifs Q (red, only present in DEAD box proteins), I, Ia, Ib, Ic, II, III, IV, Iva, V, and VI that mediate ATP binding and hydrolysis, RNA binding, and coupling of the nucleotide cycle to helicase activity. The * denotes that the Q-motif is specific for DEAD box proteins, but absent in DExH box proteins. The helicase core is often flanked by N- and C-terminal extensions (NTE, CTE). (B) Open and closed conformations of DEAD and DExH box proteins. The crystal structures of eIF4A-III (left, PDB-IDs 2HXY and 2HYI) and DENV NS3 helicase (right, PDB-IDs 2JLQ and 2JLV) in the open conformation in the absence of ligands (top), and in the closed conformation in the ternary complex with nucleotide (ADPNP) and RNA (bottom). The conserved motifs are depicted in space-filling representation in the same color code as in A, the bound RNA and ADPNP are depicted in dark yellow. In DEAD box proteins, the inter-domain cleft is wider than in DExH proteins, and the conformational change upon binding of ATP and RNA is larger. DEAD box proteins bind single stranded RNA in a bent form, whereas RNA bound to DExH box proteins is extended. (C) Model for the catalytic cycle of RNA unwinding in DEAD and DExH box proteins. Left: DEAD box proteins adopt an open conformation in the absence of ligands (1). Binding of RNA and ATP to DEAD box proteins causes the formation of a closed conformer, forming the active site for ATP hydrolysis and the bipartite RNA binding site. In this state, the bound RNA is distorted and locally destabilized (2). From an activated complex (3), the first RNA strand can dissociate. After ATP hydrolysis (4,5), phosphate release is coupled to a re-opening of the cleft in the helicase core, and the dissociation of the second RNA strand (5 to 6). Exchange of ADP for ATP starts a second catalytic cycle. Right: Mechanism of HCV-NS3-mediated RNA unwinding as a paradigm for RNA unwinding by DExH box proteins that translocate along one of the strands. In the nucleotide-free state (1), the two pincer residues (orange and blue triangles) contact the RNA backbone with a distance of three nucleotides. ATP binding leads to a closure o the helicase core, and a repositioning of the pincers that have come closer (2), thereby creating tension between the helicase core and domain 3. Upon ATP hydrolysis and product release, the helicase core re-opens, and the pincers move further apart again (3). Hydrolysis of one ATP has caused a translocation of the helicase core by one nucleotide. In a subsequent ATP hydrolysis cycle, the translocation is repeated (4,5), further increasing the tension between the core and domain 3. In a third ATP hydrolysis cycle (6,7), the advancement by a third nucleotide triggers the release of this tension (“spring-loaded” mechanism), leading to a burst of unwinding 3 base pairs (7). The N- and C-terminal domains of the helicase core (H1, H2) are depicted in orange and blue, the domain 3 of DExH proteins in yellow. ATP is shown in green. The DExH box protein pincer residues and Trp501 that has been implicated in the “spring-loaded” mechanism (see main text) are depicted as orange, blue and yellow triangles.
Helicases of the DExH box family are processive RNA helicases that translocate on RNA (reviewed in 2). By contrast, DEAD box helicases exert their function by locally destabilizing RNA duplexes, and are not processive (reviewed in3,4). DEAD box proteins constitute the largest family of RNA helicases, but their number varies among different organisms: The human genome codes for 36 putative DEAD-box helicases,5 Arabidopsis thaliana contains > 50,6 Drosophila and Caenorhabditis elegans ~30,6,7 and S. cerevisiae 25.8,9 Bacterial genomes, e.g., in E. coli and B. subtilis, code for few DEAD box helicases, whereas the genomes of Chlamydia and Borrelia lack putative DEAD box helicase genes.8 In Methanococcus, and in the archaea Pyrococcus and Halobacterium only one representative has been found.8 While the name “RNA helicase” stems from the hallmark reaction of duplex separation, many enzymes also catalyze strand exchange, strand annealing, and RNP assembly/disassembly (reviewed in 3).
1.1 Mechanism of RNA unwinding by DEAD-box proteins
The mechanism with which RNA helicases couple ATP hydrolysis to duplex separation is beginning to emerge, and is different between the SF2 families. DEAD box proteins exist in an open, “off”-state in the absence of RNA and ATP, with a wide cleft separating the two globular domains of the helicase core (Fig. 1). Cooperative binding of ATP and RNA leads to a closure of the inter-domain cleft,10 and aligns the conserved motifs of both domains, thereby creating the catalytic site for ATP hydrolysis and the RNA binding site.11 Single-stranded RNA bound to the closed conformer of the helicase is bent into a geometry that disrupts stacking of adjacent bases, and is not compatible with the canonical RNA A-form helix.11 The bend results from steric hindrance caused by a helix that contains motif Ib (Fig. 1). In DExH proteins, this helix adopts a different conformation, and the RNA is not distorted, but bound in an extended form.11,12 DEAD box proteins thus cause local duplex destabilization upon binding, and facilitate the dissociation of the first RNA strand from the helicase. Interestingly, the formation of the closed helicase conformer is also supported by non-hydrolyzable ATP analogs that do not support RNA unwinding, indicating that cleft closure is not sufficient for duplex separation to occur.13 After ATP hydrolysis and phosphate release, the helicase core returns into an open conformation. The RNA binding site is disrupted, causing RNA release, and the helicase can undergo further catalytic cycles. Notably, the mechanism of local duplex destabilization can rationalize both duplex separation and RNP remodeling activities. The alternation between open and closed conformation of the helicase core is a central feature of the RNA helicase activity in DEAD box proteins (Fig. 1), and transitions between the two states are targeted in regulatory processes. A well-studied example is the translation initiation factor eIF4A, whose activity is regulated by a number of other factors in the translation initiation network (reviewed in Ref.14). eIF4G, a scaffold protein mediating protein/protein interactions, stimulates eIF4A activity by guiding the conformational transition between open and closed states.4 In contrast, the inhibitor Pdcd4,15 and eIF4A-inhibiting aptamers,16 fix the two globular domains of the helicase core in a non-productive arrangement, and prevent conformational transitions.
Additional domains anchor the helicase core close to its target RNA by recognizing specific RNA binding sites, or by contributing to RNA binding in general. Examples are the DEAD-box proteins DbpA (E. coli) and YxiN (B. subtilis) that specifically interact with rRNA via their C-terminal RNA binding domains17,18 and are involved in ribosome assembly, the T. thermophilus protein Hera whose C-terminal RNA binding domain interacts with RNase P RNA,19,20 or yeast Mss116 that contains a basic C-terminal domain which binds RNA with low specificity, but high affinity.21 Possibly, the anchor domains remain bound to RNA during multiple catalytic cycles, rationalizing the lacking RNA translocase activities.
1.2 Mechanism of RNA unwinding by DExH box helicases
DExH proteins also consist of a helicase core with two globular domains. Structures of DExH box helicases in the absence and presence of RNA and nucleotide have shown that these domains are already closer than in DEAD box proteins in the absence of substrates.22 Similar to DEAD box proteins, ATP and RNA binding to DExH proteins promote the formation of a closed conformer, although the conformational changes are smaller (Fig. 1). In contrast to DEAD box proteins, DExH box proteins have been shown to translocate along (single- or double-stranded) RNA.23,24 While DEAD-box proteins can initiate duplex separation on blunt-ended RNA substrates and internally,25 DExH-box proteins need a single-stranded RNA-region for loading onto their substrate.26 In contrast to DEAD box proteins, the RNA bound to the DExH box helicase core is not significantly distorted, and neighboring bases remain stacked.12 This difference is in-line with a different position of the helix that causes RNA distortion in DEAD box proteins.11
Two mechanistic models, the Brownian motor model and the stepping motor (inchworm) model, have been put forward for translocation and duplex separation by DExH box proteins, both predominantly based on studies of the paradigm representative, Hepatitis C Virus NS3 (HCV-NS3) helicase (see section 2.1). Both models rationalize duplex unwinding in accordance with experimental data. The Brownian motor model is widely applicable to directional movement of motors on a track (reviewed in27), and explains directional translocation of a helicase along the asymmetric nucleic acid track by a switch between high-affinity and low-affinity states. HCV-NS3 exhibits high affinity for nucleic acid in the absence of ATP, with a preference for single-stranded/double-stranded junctions, and a low affinity in the presence of ATP.28 ATP binding thus switches the helicase core to a low-affinity state, and loosens the grip on the nucleic acid, whereas ATP hydrolysis and nucleotide release causes a switch back to high nucleic acid affinity. The stepping motor-model also takes into account the different helicase conformations in the presence and absence of ATP, and their interaction with the nucleic acid track. In HCV NS3, two threonine residues (“pincers”) in the helicase core domains contact the RNA backbone (see below, Ref.12). The contact sites are three nucleotides apart in the absence of ATP, but only two nucleotides apart in the ATP-bound state.12 According to the stepping motor-model, the alternation between these two states leads to the translocation by one nucleotide in each step (Fig. 1, see section 2.1).
DEAD and DExH box RNA helicases take part in a variety of complex cellular processes, and have been implicated in viral and other infections, in neurological disorders, cancer and aging. This review summarizes our current knowledge on the role of RNA helicases in disease (summarized in Table 1), and illustrates the potential of targeting RNA helicases for therapeutic applications. Understanding the molecular mechanism of RNA helicases is critical for understanding these diseases, and for the generation of mechanism-based inhibitors to treat helicase-related diseases.
Table 1. RNA helicases involved in infection and disease
2. Viral infections
Viral infections cause acute diseases, and are responsible for ~20% of human cancers. In addition, they have been implicated in the etiology of neurological disorders and chronic diseases (reviewed in29). About 80% of all viruses are RNA viruses. RNA helicases are required for the life cycle of RNA- and retroviruses, but also for DNA viruses, and play multiple roles in host/pathogen interactions in general. Most RNA viruses contain a RNA helicase of their own, whereas retroviruses lack a helicase, and instead hijack cellular RNA helicases to support their life cycle (Fig. 2). Intriguingly, RNA helicases also play central roles in the antiviral defense mechanism. The role of RNA helicases in viral infections has recently been reviewed,30 and is therefore only summarized briefly here, with a focus on novel findings.
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01 June 2012Figure 2. Retroviral life cycle and the role of host helicases. Viruses enter the cell by membrane fusion. Reverse transcriptase catalyzes the RNA-dependent DNA-synthesis of the reverse-transcribed genome that is integrated into the host DNA. Transcription, splicing and nuclear export generate mRNAs for viral proteins that are translated in the cytoplasm. Viral particles are assembled from capsid proteins, reverse transcriptase and the genomic (+)-strand RNA, and exit the cell by budding from the membrane. Host RNA helicases involved in the individual processes are highlighted (see text for details).
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/krnb20/2012/krnb20.v009.i06/rna.20090/20141027/images/medium/krnb_a_10920090_f0002.gif"})
Figure 2. Retroviral life cycle and the role of host helicases. Viruses enter the cell by membrane fusion. Reverse transcriptase catalyzes the RNA-dependent DNA-synthesis of the reverse-transcribed genome that is integrated into the host DNA. Transcription, splicing and nuclear export generate mRNAs for viral proteins that are translated in the cytoplasm. Viral particles are assembled from capsid proteins, reverse transcriptase and the genomic (+)-strand RNA, and exit the cell by budding from the membrane. Host RNA helicases involved in the individual processes are highlighted (see text for details).
2.1 Viral helicases
Most RNA viruses carry one or more helicase genes, and depend on these helicases for replication (reviewed in30,31). The best-studied examples are the hepatitis virus C NS3 helicase(HCV-NS3), a DExH family member that is essential for HCV replication,32 and the poxviral nucleoside triphosphate phosphohydrolase-II (NPH-II), a DEVH box helicase similar to HCV-NS3 that processively unwinds RNA or DNA/RNA hybrids.33
The HCV-NS3 helicase as a prototype for viral NS3 helicases
HCV, the causative agent of hepatitis C, belongs to the family of Flaviviridae. HCV is a single-(+)-stranded RNA virus that does not integrate its genome into the host DNA. Instead, a viral RNA polymerase (NS5) transcribes the positive-strand genome into negative-strand mRNA for the translation of viral proteins. The HCV-NS3 helicase is a processive helicase that unwinds dsRNA and RNA/DNA-hybrids in a 3′- to 5′-direction.24,28 In HCV, it unwinds RNA structures during RNA-dependent RNA-replication, and assists in viral assembly.34 Its function cannot be replaced by cellular helicases. The HCV helicase is part of the HCV NS3 protein, a fusion of an N-terminal serine protease module and the C-terminal helicase module. The structure of full-length HCV-NS3 and of the isolated helicase has been determined in the absence of DNA,22,35 in complex with ssDNA,36 in complex with DNA and different nucleotides,37 as well as in complex with inhibitors.38 The HCV-NS3 helicase consists of two RecA domains (domains H1 and H2) and a third α-helical domain (domain 3) (Ref,22Figure 3). In the full-length protein, the helicase domains are packed onto the protease, and the C-terminus binds to the protease active site.35 The DNA binds into a channel between the RecA domains and domain 3, with H1 contacting the 3′-end and H2 contacting the 5′-end.36,37 HCV-NS3 only forms specific contacts with the DNA backbone. In the nucleotide-free state, the “bookend” residues V432 (in the domain H2) and W501 (in domain 3) stack onto bases on either ends of a five-nucleotide-stretch (Fig. 3). Within this stretch, neighboring bases are stacked.
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01 June 2012Figure 3. Structures of viral NS3 helicases. (A) Overview, JEV: Japanese encephalitis virus (PDB-ID 2Z83), MEV: Murray Valley encephalitis virus (PDB-ID 2V8O), KUNV: Kunjin virus (PDB-ID 2QEQ), YFV: Yellow fever virus (PDB-ID 1YKS), DENV: Dengue virus (PDB-ID 2JLV), HCV: Hepatitis C virus (PDB-ID 3O8R). The domains are shown in orange (H1), blue (H2) and yellow (domain 3). (B) Close-up of superimposed structures. Pincer residues Thr269 and Thr410 and bookend residues Val 432 and Trp501 are depicted in stick-representation (black). The residues corresponding to the pincer residues in HCV-NS3 (Cys262 and Thr409 in JEV-NS3, Cys262 and Thr409 in MEV-NS3, Cys262 and Thr410 in KUNV-NS3, Cys266 and T413 in YFV-NS3, Cys261 and Thr408 in DENV-NS3) and to the bookend residue Val432 in HCV-NS3 (Val430 in JEV-NS3, Val430 in MEV-NS3, Val430 in KUNV-NS3, Phe434 in YFV-NS, Leu429 in DENV-NS3) are depicted in gray. Trp501 is unique to HCV-NS3, and has been linked to the unwinding of RNA in bursts of three base-pairs. The corresponding positions of the other mechanistically important residues in all helicases suggest similar translocation mechanisms.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/krnb20/2012/krnb20.v009.i06/rna.20090/20141027/images/medium/krnb_a_10920090_f0003.gif"})
Figure 3. Structures of viral NS3 helicases. (A) Overview, JEV: Japanese encephalitis virus (PDB-ID 2Z83), MEV: Murray Valley encephalitis virus (PDB-ID 2V8O), KUNV: Kunjin virus (PDB-ID 2QEQ), YFV: Yellow fever virus (PDB-ID 1YKS), DENV: Dengue virus (PDB-ID 2JLV), HCV: Hepatitis C virus (PDB-ID 3O8R). The domains are shown in orange (H1), blue (H2) and yellow (domain 3). (B) Close-up of superimposed structures. Pincer residues Thr269 and Thr410 and bookend residues Val 432 and Trp501 are depicted in stick-representation (black). The residues corresponding to the pincer residues in HCV-NS3 (Cys262 and Thr409 in JEV-NS3, Cys262 and Thr409 in MEV-NS3, Cys262 and Thr410 in KUNV-NS3, Cys266 and T413 in YFV-NS3, Cys261 and Thr408 in DENV-NS3) and to the bookend residue Val432 in HCV-NS3 (Val430 in JEV-NS3, Val430 in MEV-NS3, Val430 in KUNV-NS3, Phe434 in YFV-NS, Leu429 in DENV-NS3) are depicted in gray. Trp501 is unique to HCV-NS3, and has been linked to the unwinding of RNA in bursts of three base-pairs. The corresponding positions of the other mechanistically important residues in all helicases suggest similar translocation mechanisms.
Mechanism of HCV-NS3 translocation on RNA
The translocation mechanism of HCV-NS3 has been studied extensively in biochemical, crystallographic and single molecule experiments (reviewed in2,39). HCV-NS3 unwinds RNA by actively destabilizing the duplex.28,40 A conserved β-hairpin assists in duplex separation and provides directionality.41,42 Structures of the HCV-NS3 helicase in complex with ssDNA in the absence of nucleotide, and in the presence of ground-state and transition-state ATP mimics ADP·BeF3- and ADP·AlF4-,37 have provided snapshots of intermediates of the nucleotide cycle during translocation on ssDNA. HCV-NS3 binds nucleotides in a cleft between the two RecA domains, causing a closure of the cleft.37 The nucleotide is contacted by the canonical motifs I-III, V, and a newly discovered Y motif located between motifs Ia and Ib. A Tyr in the conserved Y motif sandwiches the adenine jointly with a Thr from motif V without recognizing the base, rationalizing why NS3 accepts any nucleotide.43 Likewise, the 2’-hydroxyl of the ribose is not contacted, in-line with the finding that dNTPs and NTPs are hydrolyzed.43 Comparison of the structures in the absence of nucleotide and in complex with ADP·BeF3- and ADP·AlF4- reveal three distinct structural states.37 Nucleotide binding provokes a series of structural transitions, involving a rotation of H1 and domain 3, and a rearrangement of motif V. When the enzyme proceeds to the transition state, H1 and domain 3 rotate further, mainly involving motif II in the ATPase site. This conformational change and causes an extension of the α-helix carrying the Y motif (“spring helix”), and positions its N-terminus closer to the bound ssDNA. As a consequence, the phosphate from nucleotide 3, previously contacted by residues from the H1 domain, is “handed over” to the H2 domain. The conformation of the bound ssDNA is also affected: The segments flanking base 1 rotate upon DNA binding and cleft closure, and the DNA is slightly bent. The rotation of the DNA ends progresses as hydrolysis proceeds. From the changes in phosphate contacts, sugar pucker and base conformations, the authors suggest that the fifth base of the stacked row that packs against Trp501 will be released and replaced by the fourth base upon ATP binding. After product release, a base liberated from the duplex region may then join the stack, and complete the ratchet-like movement of NS3 by one nucleotide.37
A recent structural study has addressed the translocation of HCV-NS3 on its natural substrate RNA (,12 see Figure 1). ssRNA is bound in a similar fashion as ssDNA, with five consecutively stacked nucleotides between the “bookend” residues. H2 interacts with the 5′-end of the RNA, and the 3′-end is engaged in contacts with residues from H1 and domain 3. The A-form geometry of RNA, however, causes a shorter distance between adjacent phosphates than in DNA, a difference that is compensated for by local structural rearrangements and inter-domain flexibility.12 The RNA 2’-hydroxyl groups are not contacted by NS3.
Structures of HCV-NS3 in complex with bromine-labeled RNA allowed tracking of the position of the bound RNA during two consecutive nucleotide cycles.12 Upon binding of ADP·BeF3-, H2 pivots toward H1, and the “spring helix” in H1, containing residues from motif Ia at the N- and the Y-motif at its C-terminus, is tilted toward H2. A conformational change in motif V moves Thr416 away from the RNA backbone, and the overall number of contacts with the bound RNA is reduced,12 in agreement with the loss of RNA affinity for the nucleotide-bound state (,28 see Brownian motor model above). Only four bases are stacked in the nucleotide-bound state. Thr411 (H1) and Thr269 (H2), the pincer residues (see stepping motor model above), contact the phosphodiester backbone, with a distance of two nucleotides in the nucleotide-bound state, and three nucleotides in the nucleotide-free state. ATP hydrolysis drives the transition between these two states, and the ATP-driven conformational changes couple the hydrolysis of one ATP hydrolysis event to the translocation of HCV-NS3 along the RNA backbone by one base pair. Single molecule experiments have shown that HCV-NS3 unwinds RNA in bursts of three nucleotides, with single nucleotide substeps (Refs,23,24Figure 1), and have linked Trp501 outside the helicase core to opening of the RNA duplex in three base-pair increments.23 The Trp501 side-chain is stacked onto the base at the end of the bound region (“bookend,”36, see above), leading to increasing tension between the core and domain 3 while the core moves. Strikingly, structures of the NS3/RNA complexes show that the 3′-end of the RNA does not move relative to this conserved Trp501 residue while the domain 2 moves along the RNA by one nucleotide per ATP hydrolyzed,12 in agreement with its role as an anchor in the “spring-loading” mechanism (Fig. 1, see above), and support a spring-like contraction after three base-pairs, that pulls domain 3 toward the core, leading to a burst of duplex separation.
The structures for HCV-NS3,22,35 and other NS3 proteins determined to date, such as the homologs in yellow fever virus,44 Dengue virus,42,45 and Murray Valley encephalitis virus46,47 are similar, and the key residues in the unwinding mechanism are conserved, suggesting a common translocation mechanism (Fig. 3).
The poxviral NPH-II helicase
RNA helicases also play a crucial role in the life cycle of DNA viruses. The vaccinia virus, a dsDNA virus of the Poxviridae family, relies on its RNA helicase NPH-II during replication.48 NPH-II is a DEVH box helicase similar to the HCV-NS3 helicase that processively unwinds RNA or DNA/RNA hybrids.33 The enzyme unwinds dsRNA during viral transcription.49 NPH-II is incorporated into vaccinia virions and required for infectivity.50
Due to their essential function for the viral lifecycle, viral helicases are potential targets for the treatment of viral infections (see section 8).
2.2 Host helicases as co-factors in the viral life cycle
Viruses that do not encode an RNA helicase abduct cellular helicases to support their lifecycle and to promote infectivity. A number of host RNA helicase genes have been identified that alter their expression level upon viral infection (reviewed in30). Host RNA helicases are involved in virus entry by receptor mediated endocytosis, in reverse transcription and integration into the host genome, in transcription, RNA processing and export from the nucleus, in polysomal translation, and in viral assembly (reviewed in30) A prime example is the retrovirus HIV-1. Lacking an RNA helicase of its own, HIV-1 recruits cellular helicases to support reverse transcription, transcription, and nuclear export (Fig. 2, 4; reviewed in31), and a number of human DEAD box helicase genes have been identified that change their expression pattern after infection.51
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01 June 2012Figure 4. Schematic overview of the domain structure of host RNA helicases involved in the viral life cycle and the innate antiviral immune response. H1, H2: helicase core domains I and II, SPRY: protein-protein interaction domain (domain in SPla and the RYanodine Receptor), HA2: Helicase associated domain, OB/NTD: oligonucleotide/oligosaccharide-binding domain, dsRBD: dsRNA binding domain, CARD: caspase recruitment domain, RD: regulatory domain.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/krnb20/2012/krnb20.v009.i06/rna.20090/20141027/images/medium/krnb_a_10920090_f0004.gif"})
Figure 4. Schematic overview of the domain structure of host RNA helicases involved in the viral life cycle and the innate antiviral immune response. H1, H2: helicase core domains I and II, SPRY: protein-protein interaction domain (domain in SPla and the RYanodine Receptor), HA2: Helicase associated domain, OB/NTD: oligonucleotide/oligosaccharide-binding domain, dsRBD: dsRNA binding domain, CARD: caspase recruitment domain, RD: regulatory domain.
Host helicases in HIV-1 infection
HIV-1 gene expression is regulated on the transcriptional and post-transcriptional level by the viral proteins Tat and Rev that interact with a variety of host cellular factors. The HIV-1 Rev protein binds to the Rev responsive element (RRE) of the HIV-1 mRNA, and promotes the export of incompletely spliced mRNAs from the nucleus,52 allowing for the expression of late-stage genes and the production of genomic RNA for packaging. The cellular helicases DDX1 and DDX3 are involved in the regulation of HIV-1 gene expression at the end of the viral life cycle through interactions with Rev. In the human host, DDX1 (Fig. 4) functions in transcription,53,54 pre-mRNA processing55,56 and mRNA translation.57 It interacts with the oligomerization domain of HIV-1 Rev,58 and promotes Rev-oligomerization on the RRE.59 The binding of DDX1 to Rev may target DDX1 to incompletely spliced transcripts.60 DDX1 has also been associated with the lifecycle of polyoma and coronaviruses,61,62 and of HCV.63 Similar to DDX1, DDX3 enhances the Rev-dependent export of unspliced transcripts from the nucleus,64 presumably by acting as a nucleo-cytoplasmatic shuttle protein. DDX3 is located at the nuclear pore complex64 and interacts with the nuclear export receptor CRM-164 that is required for Rev-mediated nuclear export of HIV-1 RNAs. In addition to DDX1 and DDX3, a recent proteomics study searching for host factors interacting with HIV-1 Rev65 identified the DExD/H box helicases DHX36, DDX24, DDX17, DHX9, DDX47, and DDX5 as Rev binding partners. This study also linked DDX5 and DDX17 to the production of HIV-1 virions in a cell model, and demonstrated effects on splicing and transcript localization in infected cells where DDX5, DDX17, or DDX21 were silenced.
The helicase DHX9 (RHA/NDHII) consists of a DEIH helicase core, flanked by N-terminal dsRNA binding domains (Fig. 4) plus a nuclear transport domain and C-terminal RGG repeats (Ref.66). In the nucleus, DHX9 interacts with RNA polymerase and transcription factors thereby regulating transcription.67 DHX9 is implicated in the replication cycles of HIV-1 and of retroviruses in general, and also of flavi- and adenoviruses.31,68-70 In HIV-1, DHX9 is associated with the viral gag protein, and encapsulated into virions.71 Viral particles lacking DHX9 are less infectious and show reduced reverse transcriptase activity, implicating DHX9 in reverse transcription. DHX9/RHA is also involved in transcription and translation of viral mRNAs. It interacts with the long-terminal repeats and with the 5-UTR,72 and facilitates ribosomal scanning and translation initiation by rearranging the involved RNPs.73 In retroviruses that do not encode a Rev-like protein, DHX9 acts similar to the retroviral Rev protein by mediating nuclear export of unspliced RNA transcripts.72 DHX9 also plays an essential role in replication of foot-and-mouth-disease virus (FMDV), a pathogenic RNA virus that infects horn-hoofed animals.74 Infection of cells with FMDV changes the cellular localization of DHX9 from the nucleus to the cytoplasm.75 DHX9/RHA interacts with the internal ribosome entry site of FMDV and HCV mRNA,76 and with FMDV proteins involved in assembly of replication complexes.75 Recently, a role of DHX9/RHA for the influenza viral life cycle has been demonstrated,77 where it enhances transcription and replication.
DDX6
(RCK/p54), a translational repressor, proto-oncogene, and cell cycle regulator,78 negatively regulates HIV-1 replication,79 and is required for genome encapsidation, but is not encapsulated into virions.80 Its functions in viral replication require its ATPase and helicase activities.80 After infection with foamy viruses, retroviruses which infect non-human primates, DDX6 re-localizes from P bodies and stress granules to the viral assembly site.80 DDX6 has also been implicated in efficient HCV replication.81
2.3 Host helicases involved in the innate anti-viral immune response
Sections 2.1 and 2.2 illustrate how cellular RNA helicases support the viral life cycle and promote viral infection. Intriguingly, vertebrate RNA helicases also play a central role in antiviral defense mechanisms. The RIG-I-like receptors RIG-I (retinoic acid inducible gene), MDA-5 (melanoma differentiation-associated gene 5), and LGP2 (laboratory of genetics and physiology 2)84,85 are cytoplasmic DExD/H box proteins that trigger the innate immune response to RNA virus infections of vertebrates. Within the DExD/H box family, their conserved sequence motifs put them into the Dicer/RIG-I clade that comprises Dicer, a 220 kDa DECH box protein that generates microRNAs, and other proteins involved in gene silencing.86 MicroRNA-mediated regulatory mechanisms have also been implicated in the innate antiviral immune defense.87,88 The RIG-I-like receptors share a common domain structure (Fig. 4) with two N-terminal caspase activation and recruitment domains (CARDs), a DECH box RNA helicase domain, and a C-terminal domain (CTD; auto-repressing regulatory domain). LPG-2 is lacking the CARD domains and has been suggested to regulate the antiviral response induced by RIG-I and MDA-5,89 but its role in antiviral defense is not entirely clear. In contrast, the function of RIG-I (DDX58) in antiviral defense has been studied in detail. The RIG-I helicase domain binds dsRNA, and the CTD binds the 5′-triphosphate end.90,91 The two N-terminal CARDs functionally connect RIG-I to the caspase signaling cascade. The CTD mediates auto-repression of RIG-I activity in the absence of non-self RNAs. The general mechanism (reviewed in,92 see also references therein) is as follows: In the cell, RIG-I occurs in an autoinhibited state that is activated upon binding of non-self, viral RNAs containing a 5′-triphosphate. Upon activation, the CARDs are ubiquitinylated,93 and mediate the recruitment of the adaptor protein IPS-1 (interferon-β promoter stimulator) on the mitochondrial outer membrane. As a result, a signaling cascade leads to the phosphorylation and activation of transcription factors IRF3, IRF7, NF-κB. Together, these factors coordinate the expression of interferon and interferon-stimulated genes,94 and the production of type-1 interferons, and pro-inflammatory cytokines.95 Interestingly, the expression of NF-κB- and α-interferon-dependent genes is also affected through the RNA helicase DHX9.96,97 The RIG-I CARDs are necessary and sufficient for signaling: Their overexpression leads to signaling, whereas a truncated RIG-I construct devoid of CARDs is a dominant negative signaling inhibitor.98 RIG-I and MDA-5 elicit the antiviral response via the same pathway, but recognize different RNAs99: RIG-I senses a number of positive and negative strand RNA viruses, such as influenza virus, whereas MDA-5 detects different positive strand and dsRNA viruses (reviewed in100). Interestingly, RIG-I is not present in chicken, which may explain their high susceptibility to influenza virus.101 Several viruses have developed mechanisms to counteract RIG-I signaling (reviewed in95,102). Examples are Paramyxovirus, whose V protein binds to mammalian MDA-5, blocks its activation of the IFN-β promoter and thus prevents the antiviral interferon response,103 and HCV, whose NS4/NS3 protease cleaves the adaptor protein IPS-1.104
The structural basis for RIG-I mediated signal transduction
Recent structural data on RIG-I86,105 have delineated the molecular mechanism for sensing viral RNAs and for RIG-I mediated signal transduction (Fig. 5). The helicase core of RIG-I adopts an open conformation in all determined structures in the absence of ligands.105 Differences in the relative orientation of the two RecA domains (H1, H2) point toward considerable flexibility. The H2 domain of RIG-I contains an insertion (H2i) that forms a α-helical bundle. A bridging domain, or “pincer,” formed by two α-helices adopting a V-shape, connects H2 with the CTD.86,105 It folds back to H1 and firmly contacts an α-helix inserted after motif III (that is involved in coupling ATP hydrolysis to RNA unwinding) via an interaction network involving conserved residues that have shown to be important for the RIG-I-mediated interferon response (,86 see below).
Published online:
01 June 2012Figure 5. RIG-I as a sensor of viral RNA in the innate antiviral immune response. (A) Domain structure of RIG-I The helicase core is depicted in orange and blue, the connecting domain (bridge/pincer) in pink, the H2i domain in light blue, the N-terminal CARDs in light and dark green, and the CTD in yellow. The bound RNA is shown in green. (B) Structure of the autorepressed state of RIG-I in the absence of RNA and nucleotide (PDB-ID 4A2W). The helicase core is in an open conformation. The CARDs are in contact with H2i. The unresolved linker connecting CARD2 and H1 is indicated by a dashed black line. The CTD has not been resolved in this structure. (C) Structure of RIG-I (lacking the CARDs, PDB-ID 4A36) in complex with dsRNA and ADPNP. The helicase domain adopts a closed conformation, and the H2i domain contacts the RNA from the side. (D) Model of activated RIG-I in complex with dsRNA, generated by superimposing the structures of RIG-I in complex with ADPNP and RNA (PDB-ID 4A36, panel c) and of the CTD in complex with RNA (PDB-ID 4A2X) on the RNA. The RNA is engulfed by the helicase domains, the H2i domains and the CTD. The missing linker between the bridging/pincer domain and the CTD is indicated by the dashed black line. (E) Cartoon highlighting the conformational changes in RIG-I during the transition from the autorepressed state (left) to the active, signaling state (right). The color code is the same as in panels a to d. ATP is depicted as a dark green square, RNA as a dark green circle.
![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/krnb20/2012/krnb20.v009.i06/rna.20090/20141027/images/medium/krnb_a_10920090_f0005.gif"})
Figure 5. RIG-I as a sensor of viral RNA in the innate antiviral immune response. (A) Domain structure of RIG-I The helicase core is depicted in orange and blue, the connecting domain (bridge/pincer) in pink, the H2i domain in light blue, the N-terminal CARDs in light and dark green, and the CTD in yellow. The bound RNA is shown in green. (B) Structure of the autorepressed state of RIG-I in the absence of RNA and nucleotide (PDB-ID 4A2W). The helicase core is in an open conformation. The CARDs are in contact with H2i. The unresolved linker connecting CARD2 and H1 is indicated by a dashed black line. The CTD has not been resolved in this structure. (C) Structure of RIG-I (lacking the CARDs, PDB-ID 4A36) in complex with dsRNA and ADPNP. The helicase domain adopts a closed conformation, and the H2i domain contacts the RNA from the side. (D) Model of activated RIG-I in complex with dsRNA, generated by superimposing the structures of RIG-I in complex with ADPNP and RNA (PDB-ID 4A36, panel c) and of the CTD in complex with RNA (PDB-ID 4A2X) on the RNA. The RNA is engulfed by the helicase domains, the H2i domains and the CTD. The missing linker between the bridging/pincer domain and the CTD is indicated by the dashed black line. (E) Cartoon highlighting the conformational changes in RIG-I during the transition from the autorepressed state (left) to the active, signaling state (right). The color code is the same as in panels a to d. ATP is depicted as a dark green square, RNA as a dark green circle.
In the complex of RIG-I with dsRNA and the transition state analog ADP·AlF3- and dsRNA (Fig. 5), the RIG-I helicase core adopts a closed conformation.105 The insertion H2i has rotated away from H2, and now flanks the bound dsRNA. The helicase core forms an extensive interaction network with the bound RNA via the canonical motifs, mainly with 2’-OH groups, rationalizing the inhibition of RIG-I by RNAs with 2’-OH modifications.106 H1 contacts both RNA strands, and a stretch of amino acids from H2i forms a concave binding platform for the second RNA strand, explaining dsRNA specificity.86,105 A similar insertion in Dicer may also mediate duplex recognition.86 In contrast to DEAD box proteins,11 but similar to viral DExD/H box proteins,12,36 the bound dsRNA adopts A-form geometry without any indication of destabilization or unwinding.86,105
The CTD is not visible in the electron density of full-length RIG-I, suggesting that it is flexibly linked to the remainder of RIG-I.105 Nevertheless, the combination of structural information from different constructs has provided models for RIG-I in its inactive, auto-repressed state and in the activated, RNA-bound state (Fig. 5). Comparison of these structures reveals RNA-induced conformational changes of RIG-I that had been inferred from limited proteolysis107 and SAXS experiments.86 A model for auto-repressed RIG-I in the absence of RNA emerges from the structure of RIG-I lacking the CTD (Fig. 5; Ref.105). The CARDs interact intimately with each other and possibly form a rigid functional unit,105 rationalizing the previous observation that a CARD dimer is required for signaling.93 The CARDs block RNA binding to RIG-I by interacting with H2i via the α-helix that is critical for dsRNA binding. The ubiquitination site of the CARDs points toward the helicase core, providing little space for the attachment of ubiquitin chains.105 A structural model of full-length RIG-I in the activated state can be constructed from the structures of the RIG-I helicase domain in complex with dsRNA105 in combination with the structure of the RIG-I CTD/RNA complex105 or the RNA complex of RIG-I lacking the CARDs86 (Fig. 5). In these structures, the dsRNA is surrounded by RIG-I domains, in-line with large conformational changes of RIG-I upon RNA binding. The helicase domain binds to the 3′-end of the RNA, and the CTD contacts the 5′-end and the triphosphate moiety.105 The CTD structure is similar to previously determined CTD and CTD/RNA structures.108,109 The interaction site on H2i for the CARDs is now bound to RNA. As a consequence, the CARDs will be released and become available for modification and signaling.
The pincer/bridge domain does not interact with RNA, but tightly connects the helicase domains H1, H2 and the CTD. Mutagenesis of residues in this domain eliminate coupling between RNA binding and ATP hydrolysis, and reduce or abolish the RNA-dependent interferon response,86 supporting an important role in coordinating structural rearrangements within RIG-I.86,110
In summary, the structures of RIG-I provide a molecular model for RIG-I-mediated sensing of viral RNAs and signal transduction: In the autoinhibited state, the helicase domain is in an open conformation, with low affinities for ATP and RNA. The CARD2/H2i interaction blocks the RNA binding site, and prevents ubiquitination. The CTD is flexibly linked to RIG-I. Binding of the 5′-ppp-end of dsRNA to the CTD initiates RIG-I activation, and RNA binding to the adjacent helicase core triggers closure. Release of the CARDs makes them accessible for ubiquitination, and allows for signaling. Despite the sudden wealth of structural information, the precise role of ATP hydrolysis in RIG-I signaling remains elusive. ATP may be required to drive the conformational switch of the helicase core that regulates the exposure of the CARDs for signaling,86 or it may promote the ATP-dependent translocation on RNA.111 The role of the translocation activity for signaling is unknown. Similarly, it is currently unclear how the active state of RIG-I is switched off. ATP hydrolysis and phosphate release will lead to opening of the cleft in the helicase core4,10,112 and a reduction of its RNA affinity, but the 5′-ppp-end of viral RNAs will remain anchored to the RIG-I CTDs during the ATPase cycle. Rebinding of the CARDs to their interaction site on H2i, and thus the return to the autorepressed state, are only possible once the ubiquitin modification has been cleaved. Hence, it is likely that RIG-I undergoes ATP hydrolysis cycles until the ubiquitin moiety is cleaved off the CARDs, leading to RIG-I inactivation.
3. Protozoic, bacterial and fungal infections
Several case studies suggest that DExD/H box helicases may be important players in infections in general. The parasitic pathogen Trypanosoma cruzi causes Chagas disease in humans, a disease that often remains asymptomatic, but may cause severe, in some cases fatal heart or digestive problems. The T: cruzi DEAD box helicase HelTc is upregulated in the trypomastigote, the infective life form.116
In Helicobacter pylori, a gram-negative bacterium in the stomach of humans that has been linked to chronic gastritis and gastric ulcers, the helicase DeaD may play a role in upregulation of urease activity117 and thus in gastric cancers.118
The spirochete Borrelia burgdorferi causes Lyme disease. Humans contract the disease via infected ticks. The disease starts with fever and headache, causes a characteristic erythema migrans, and ultimately leads to heart problems, pain in the joints and neurologic symptoms (Lyme borreliosis). HrpA, a DEAH box protein, is the only putative helicase in B. burgdorferi. Its E. coli homolog is involved in mRNA processing.119 Disruption of B. burgdorferi hrpA leads to a loss of infectivity in mice,120 suggesting an important role of HrpA in infection. However, the infectivity could not be restored by complementation with a wild-type hrpA gene.120 In the absence of HrpA, 90 B. burgdorferi proteins are down-, and 97 are upregulated. The most prominent group of upregulated proteins is associated with protein synthesis, while others affect the cell envelope, transcription and the fate of proteins.120 Based on these findings, HrpA has been proposed as an important hub of a global regulatory pathway in B. burgdorferi gene expression.120 HrpA orthologs are present in many bacteria, and may be general regulators.120 It remains to be seen, however, if the role of HrpA for infectivity and regulation is related to its helicase activity, as yet, no in vitro helicase activity has been reported. The downregulation of transport system components may compromise the survival of B. burgdorferi in mouse, possibly contributing to loss of virulence.120
The chronic human disease Cryptococcosis is caused by the environmental fungus Cryptococcus neoformans, and set off by the inhalation of cells or spores into alveoloar spaces. In later stages, C. neoformans spreads into the central nervous system, and leads to meningoencephalitis. The disease requires life-long treatment as no eradication therapy is available. It predominantly affects immuno-compromised individuals, but infection of immuno-competent hosts also occurs. In an effort to identify novel therapeutic targets, a random mutagenesis screen for defects in the virulence factor laccase has led to the identification of Vad1 (virulence-associated DEAD-box RNA helicase).121 Vad1 deletion causes a tremendous reduction of Cryptococcus virulence in a mouse model,121 which can be restored in complementation experiments with wild-type Vad1. The Vad1 helicase core belongs to the RCK/p54 subfamily of DExD/H box proteins that are implicated in mRNA decapping and deadenylation.122 A helicase function has not yet been demonstrated for Vad1, but its cytoplasmic localization suggests a role in mRNA stability.121 In addition, the loss of Vad1 causes upregulation of NOT1 expression,121 a component of the CCR-negative on TATA-less (Ccr4-Not) complex123 that acts as a global regulator of transcription and mRNA stability and may be implicated in the sensing of stress in the host environment.124 Vad1-dependent genes code for proteins involved in processes crucial to survival in the host environment, such as gluconeogenesis, mitochondrial function, and cell wall integrity.121 Vad1 also promotes pathogenesis by promoting the expression of virulence factors, and has thus been suggested to act as a master regulator of cryptococcal virulence.
It can be expected that the list of RNA helicases involved in infections will grow with future genome-wide studies. Mechanistic studies will identify the precise role of these helicases in the host/pathogen interaction, forming the basis for rational drug development.
Neurological disorders
RNA processing events, such as alternative splicing and RNA editing, play an important role in the nervous system,125 and aberrant RNA processing has been linked to a number of neurodegenerative diseases.125,126 An extensive set of RNA helicases have been implicated in RNA processing, and linked to neurodegenerative diseases.
Amyotrophic lateral sclerosis (ALS, Lou-Gehrig’s disease) is a neurodegenerative disease that usually leads to death within 5 y after onset. Environmental and genetic factors have been implicated in ALS etiology. Many ALS-related genes code for proteins with roles in RNA processing.126 The autosomal dominant form of juvenile ALS has an onset at the age of 25 or earlier, and leads to progressive weakness of distal muscles.127Ataxia-oculomotor apraxia type-2 (AOA2,128) is an autosomal recessive neurodegenerative disease whose patients suffer from a progressive degeneration of the cerebellum, the spinal cord and peripheral nerves. AOA2 leads to ocular apraxia, cerebellar ataxia, and sensory-motor neuropathy. Both juvenile ALS and AOA2 are caused by mutations in the senataxin (SETX) gene.127,128 Senataxin is a large protein of 2700 aa that is ubiquitously expressed.127,128 It contains a C-terminal DNA/RNA helicase module with strong homology to Upf1, a SF1 helicase involved in nonsense-mediated decay,129 to IGHMBP2 (immunoglobulin Mu binding protein 2), an ATP-dependent DNA/RNA helicase,130 and to the splicing endonuclease Sen1p, a nuclear helicase involved in tRNA, mRNA and snRNA processing essential for growth.131 SETX mutations lead to increased sensitivity to hydrogen peroxide, camptothecin and mitomycin C, suggesting a role in DNA repair.132
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that leads to death in severe cases.133 The degeneration of motor neurons in the anterior horns of the spinal cord causes progressive muscular weakness, muscular atrophy and paralysis126 SMA is associated with the survival motor neuron (SMN) protein that associates with a number of other proteins, and is part of multi-protein complexes that bind directly to snRNAs. Gemin3 interacts with SMN and is the only helicase in SMN-containing complexes. The Gemin3/SMN interaction is conserved from fly to human.134 Gemin3 is required for snRNP assembly,135,136 and may be involved in miRNA regulation and in transcription.134 Gemin3-null-mice die at an early embryonic state,137 and a deletion in flies causes lethality at the larval stage.134
Spinocerebellar ataxia type-2 is caused by mutation in the ataxin-2 gene, which is implicated in cellular RNA-processing pathways and translational regulation. Ataxin-2 interacts with DDX6, a component of P bodies and stress granules.138 Both proteins colocalize within stress granules.138 DDX6 is involved in mRNA decay122 and plays an important role for the assembly of P bodies.78
Alzheimer disease (AD) is a brain disease that causes progressive dementia. The DECD box protein UAP56 is required for splicing, and involved in spliceosome assembly and mRNA export from the nucleus.139 It couples splicing and export by remaining bound to spliced mRNA, while interacting with the export protein Aly.139 UAP56 negatively regulates the production of pro-inflammatory cytokines involved in AD, and the mRNA levels of UAP56 are increased in the brains of Alzheimer patients.140,141 A polymorphism in the promoter region of the UAP56 gene has been associated with a reduced risk of AD.142
Lethal congenital contracture syndrome (LCCS) is an autosomal recessive disease that leads to fetal immobility, and to the loss of neurons (anterior horn neurons). It is caused by a mutation in the protein Gle-1 that leads to mis-splicing.143 Gle1 mediates nuclear mRNA export by interactions with the DEAD box helicase DDX19. DDX19 allows for the release of export proteins and their recycling back to the nucleus.144
The important role of RNA processing in the nervous system suggests a link between RNA helicase malfunction and neurodegenerative diseases. In many cases the evidence for the involvement of RNA helicases is circumstantial, and their role is ill-defined. Mechanistic studies are required to further our understanding of the specific role of RNA helicases in the etiology of these diseases.
5. Cancer and aging
A number of RNA helicases have been identified that show severely altered gene expression levels in cancer cells. DDX1, a helicase involved in transcription,53,54 mRNA processing55,56 and translation,57 is upregulated in neuroblastoma and retinoblastoma cell lines and tumors.145DDX5/p68, a helicase required for miRNA processing and maturation,146 is upregulated in different cancer types, among them colorectal,147 prostate148 and breast cancer,149 and affects cellular proliferation and tumor development. DDX5 knockdown leads to cytoskeleton reorganization in basal breast cancer cells via a miRNA-dependent pathway.150DDX39, a helicase associated with growth,151 telomere protection and maintenance of genome integrity,152 is upregulated in lung153 and gastrointestinal cancers.154 High levels of DDX39 are associated with metastasis and poor prognosis, rendering it a potential biomarker for gastrointestinal tumors.154 Helicases have also been implicated in oncogene translation. For example, DHX9/RHA binds to the 5′-UTR of the mRNA for the proto-oncogene junD and facilitates its translation.73
During the initiation and progression of cancer, tumor cells are growing rapidly. They maintain higher mRNA translation rates compared with quiescent or slowly replicating cells155 by a deregulation of translation initiation, and a multitude of translation initiation factors are overexpressed in transformed cells and cancers.156 Translation initiation on cap-dependent mRNAs (reviewed in14) is dependent on eIF4F, a ternary protein complex containing the DEAD box RNA-helicase eIF4A, the cap-binding protein eIF4E, and the scaffold protein eIF4G. Together with eIF3 and the polyA-binding protein, eIF4F mediates recruitment of the 43S ribosomal subunit. After scanning of the mRNA toward the start codon, the 60S ribosomal subunit is recruited, and translation can start. As initiation is the rate-limiting step for translation, inhibitors of translation initiation should affect fast-growing cells more selectively than elongation inhibitors. eIF4A is the most abundant initiation factor157 that exists in two functionally interchangeable isoforms, I (DDX2a) and II (DDX2b).158 eIF4A is required for the translation of mRNAs with highly structured 5′-UTRs, and believed to be responsible for unwinding of these structures during scanning.159 eIF4A levels are increased in melanoma cells,160 increased or decreased in human hepatocellular carcinoma,161,166 and reduced levels occur in lung, colon, and breast cancers, and in glioma.162-165 Pdcd4, a tumor-suppressor protein, interacts directly with eIF4A.167,168 Being the only eIF4F component with enzymatic activity eIF4A is an attractive drug target (reviewed in,156 see below).
Telomers are repetitive DNA sequences at the ends of eukaryotic chromsomes. Due to their incomplete replication by DNA polymerase, telomers gradually shorten during the lifetime of a cell, leading to senescence and aging (reviewed in169,170). Telomerase is an RNA/protein complex that adds telomeric repeats to chromosome ends using a sequence within its RNA subunit as a template,171 and thereby contributes to chromosome maintenance. Frequently dividing cells, including cancer cells, generally show high levels of telomerase activity.172 The telomerase RNA subunit contains guanosine-tracts that can form G-quadruplex structures. The DExH box helicase DHX36 (RHAU, G4R1), a helicase mediating the degradation of mRNAs containing AU-rich elements,173 recognizes these guanosine tracts in telomerase RNA.174,175 DHX36 has been shown to resolve G-quadruplex DNA176 and RNA175 in vitro. While these findings link DHX36 to telomere maintenance, cancer and aging, its specific role is still unclear.
6. Other diseases with possible contributions from RNA helicases
RNA helicases have been associated with autoimmune and rheumatic diseases, with spermatogenesis and infertility, and retinal diseases. The gastric antral vascular ectasia (GAVE), also called water melon stomach disease177 because of the presence of stripes in the ecstatic vascular tissue in stomach, involves gastrointestinal bleeding, and is frequently associated with autoimmune disorders.178,179 In GAVE patients, increased antibody levels against the nucleolar protein Gu, a DExD helicase similar to RNA helicase II,180 have been detected.181 Members of this family are implicated in pre-mRNA splicing, translation, ribosomal processing, cell growth and development.182
Dermatomyositis (DM) is a chronic inflammatory (rheumatic) disorder that involves muscle and skin lesions. Patients show varying degrees of pulmonary problems. Clinically amyopathic dermatomyositis (C-ADM) is a subgroup of DM, often associated with rapidly progressing interstitial lung disease (ILD). In various DM cases, increased antibody levels have been detected, with a correlation of the antibody type and the disease sub-type: The auto-antibody associated with C-ADM and ILD recognizes the RIG-I-like receptor MDA-5,183 which is involved in the innate antiviral immune response, cellular growth suppression, and apoptosis,84,99 pointing toward the involvement of viral infections in the etiology of these diseases.184 The auto-antibody/MDA-5 interaction may be useful for C-ADM and ILD diagnostics (ELISA).183
Patients suffering from the rheumatic autoimmune disease systemic lupus erythematodes (SLE) develop auto-antibodies against DHX9/RHA,185 which have not been detected in patients with other systemic rheumatic diseases.186 DHX9 is a nuclear protein with multiple functions that binds dsDNA and RNA,187,188 mRNA, and structured viral RNAs.189 It is a component of RNA polymerase II holoenzyme, and has been implicated in CREB-dependent transcription.67,190 The DHX9 auto-antibody level diminishes within a few years after disease onset, providing a serological marker for the early disease phase.186
In spermatogenesis, the temporally controlled expression of a set of genes leads to a complex differentiation process. Mitosis of spermatogonia generates primary spermatocytes, which undergo a first meiosis to secondary spermatocytes, and a second meiosis to haploid, round spermatids. Morphologic changes of these spermatids during spermiogenesis generate elongated spermatids, and finally mature spermatozoa. The gonadotropin-regulated testicular RNA helicase GRTH/DDX25 (reviewed in191,192) is a testis-specific DEAD box protein present in germ cells and Leydig cells,193 and the only known hormonally regulated helicase. Mice lacking DDX25 are sterile, and mutations that interfere with DDX25 phosphorylation lead to infertility in humans.194 DDX25 acts as a posttranscriptional regulator during germ cell development. In the absence of DDX25, the elongation of round spermatids fails, and spermatogenesis is arrested. In contrast to DDX25, the helicases MVH (mouse) and Vasa (Drosophila) that are essential for spermatogenesis, function before the meiotic division.195,196 DDX25 has also been implicated in preventing germ cell apoptosis.197 It is most closely related to DDX19, an RNA export helicase,198 and has been identified as a component of RNPs with certain mRNAs.197 Phosphorylated DDX25 is located in the cytoplasm, the non-phosphorylated form is in the nucleus.199 DDX25 may act as a shuttle protein in the nuclear transport of germ-cell specific mRNAs to the cytoplasm.199 Its association with polysomes suggests an additional role in the regulation of translation.199 GRTH/DDX25 has been associated with azoospermia and oligospermia, and provides an important link to male infertility as well as contraception.
Retinitis pigmentosa (RP) is an eye disease leading to retinal degeneration and ultimately blindness. Mutations in pre-mRNA splicing factors have been linked to RP, among them the helicase Brr2.200 Brr2 is a special helicase that contains two helicase modules that are both followed by Sec63-like domains. In the helicase N-terminal module, the conserved signature motifs are present, whereas in the C-terminal module they are more degenerate. Mutational studies have suggested that the N-terminal module may be an active helicase, while the C-terminal module provides a platform for interactions with other proteins, and regulates the activity of the N-terminal module (,201 and references therein). Brr2 is required for U4/U6 unwinding during splicing.202 Although located in the Sec63-domains, RP-linked mutations in Brr2 abolish U4/U6 unwinding.200
7. RNA helicases as drug targets
RNA helicases are useful prognostic and diagnostic markers in different types of cancer, neurodegenerative and autoimmune diseases. The central role of RNA helicases in a variety of diseases has put them into the focus as potential drug targets, and they have been recognized as suitable targets for antiviral and anti-cancer therapies.
Numerous studies have addressed the potential of HCV-NS3 as a drug target for the treatment of hepatitis C (see section 2.1), and small molecule, nucleic acid and antibody inhibitors have been evaluated.39 Dengue virus causes a hemorrhagic fever, and West Nile virus causes fever, meningitis or encephalitis. Currently, no treatment is available, and the helicases of these viruses may thus be promising targets to identify inhibitors and to develop novel therapeutic strategies (reviewed in203). Depending on whether the virus relies on virus-encoded genes or is linked to the host metabolism, antiviral therapies can either target viral or host RNA helicases (reviewed in Ref.204). Targeting cellular factors is in general less virus-specific, and may cause cytotoxicity and side-effects, or fail due to host polymorphisms. However, treatments e.g., of hypertension, congestive heart failure, myocardic infarct, breast cancer, and Alzheimer disease that target cellular enzymes are successful and demonstrate the feasibility of such an approach. To achieve specificity, differences between host and viral proteins have to be identified and exploited.204 A major advantage of targeting host factors lies with the circumvention of resistance problems due to high mutagenesis rates of viruses. Detailed knowledge of the RNA unwinding mechanism of viral and host helicases should allow for selective, mechanism-based inhibition. Several possible inhibitory mechanisms are conceivable, such as inhibition of the ATPase activity, interference with RNA binding, inhibition of coupling between ATP hydrolysis and RNA unwinding, or inhibition of the RNA translocation activity.
Treatment of HIV-1 infections
Worldwide, more than 40 million individuals are infected with HIV-1. Initial efforts to develop anti-HIV-1 therapies have focused on the viral proteins reverse transcriptase, protease and integrase as targets. The compound murabutide is an example of a drug that targets a host RNA helicase, RH116.205 The host DEAD-box proteins DDX1 and DDX3 that are required for Rev-mediated export of unspliced or partially spliced HIV-1 mRNAs from nucleus to cytoplasm are also possible drug targets. Knock-down of DDX3 does not have cytotoxic effects in cell culture, but suppresses viral replication.64 Recent studies have reported rhodanine- and triazine-based compounds,205-207 and ring-expanded nucleosides208 as DDX3 inhibitors with anti-HIV activity, as well as a small molecule that interferes with RN A binding to DDX3 and reduces the viral load of peripheral mononuclear blood cells209
Treatment of hepatitis C
More than 170 million individuals worldwide are estimated to carry HCV. Guided by the success of anti-HIV therapies with protease inhibitors, structure-based design of therapeutic drugs against HCV have also focused on the viral protease. Although all FDA-approved anti-HCV drugs target the HCV NS3 protease,210 the presence of the viral helicase NS3 and the extensive knowledge on its mechanism offer the unique possibility to directly target this viral protein in structure-based drug design approaches (reviewed in Ref.211). A recently reported structure of a protease-targeted inhibitor has revealed that this inhibitor also contacts the helicase domain,38 underlining the possibility of targeting the helicase directly. Screening of chemical libraries has identified limited numbers of weak helicase inhibitors.212 HCV helicase activity is inhibited in vitro by recombinant antibodies,213,214 by RNA aptamers215,216 and by peptides.217,218 Targeting the nucleotide binding site of HCV NS3 has proven exceedingly difficult,219 although nucleotide-mimicking competitive inhibitors have been identified.220,221 The ring-expanded nucleoside and nucleotide analogs have been shown to selectively inhibit HCV, West Nile Virus, and Japanese encephalitis virus NS3 helicases in vitro without affecting the activity of a control host helicase.222,223 Interestingly, different derivatives of these compounds showed differential effects on the three viral helicases tested, suggesting that selective inhibition is possible despite their structural similarity. The mechanism of inhibition by these and other nucleosides may involve an unidentified allosteric nucleoside binding site on the helicases. Other in vitro-inhibitor series of HCV-NS3 helicase activity include benzimidazoles,224 acyl sulfonamides,225 tropolones,226 acridons227 and triphenylmethanes.228 HCV is responsible for more than 50% of all liver cancers, and anti-HCV drugs are therefore effective against both viral infection and cancer.
Therapeutic approaches for cancer treatment: Targeting translational initiation
Cancer therapies often exploit the high demand of proliferating cells for protein synthesis. eIF4A is an RNA helicase in translation initiation, and a drug target for the treatment of cancer (reviewed in156). A number of natural compounds have been isolated that target eIF4A, among them hippuristanol (from the marine gorgonian Isis hippuris229), pateamine A (from the marine sponge Mycale230), and silvestrol (from the plant genus Aglaia231). All of these compounds are amenable to chemical synthesis.232-234 Hippuristanol is an allosteric inhibitor of RNA binding to eIF4A. It shows a 10-fold increased specificity to eIF4A-I vs. eIF4A-III due to differences in the binding pockets,158 demonstrating that selective pharmacological targeting of RNA helicases is possible.
Pateamine A shows antifungal, antiviral and immunosuppressive activity.230,234 Its cytotoxic effect is higher for transformed cells than for non-transformed cells,235 and it is toxic at low doses.156 Importantly, pateamine A is not transported by PgP, a transporter responsible for multi-drug resistance.236 Pateamine A leads to an increase in ATPase and helicase activities of eIF4A, but inhibits translation initiation irreversibly.237,238 It also induces dimerization of eIF4A,237,239 and an increase in RNA affinity237 and in the stability of eIF4A/B complex.238 Pateamine A binds to both mammalian eIF4A-I and -III,237 but does not affect splicing (which only involves eIF4A-III) suggesting specificity despite its interaction with other cellular proteins.
Aglaia plant extracts have been used for the treatment of inflammation and of bacterial infections, and as insecticides. The active compound silvestrol inhibits translation by increasing eIF4A’s RNA affinity.240 It also induces eIF4A dimerization, causing the depletion of eIF4A from eIF4F complexes.240,241 Silvestrol has proven promising as a therapeutic agent in multiple cancer mouse models, either alone or in combination with other drugs,156 and does not cause common side-effects such as distress, liver damage, or immuno-suppression in preclinical mouse models.241,242 It is effective against eIF4E-dependent lymphomas that are resistant to rapamycin,240 and as a single-agent in chemotherapies against acute lymphoblastic leukemia,242 prostate and breast cancer241 in mouse models. Leukemic or faster-growing cells are more sensitive to silvestrol than cells from healthy individuals.242
Future years will demonstrate if translation initiation targeting is a feasible approach in clinical treatment of cancers.156
Antiviral and anti-cancer therapies targeting RIG-Like receptors?
RIG-I, besides its role in antiviral defense (see above), induces apoptosis in cancer cells.243 RIG-I antagonists may thus also be suited for treatment of viral infections (see above) and cancer.244 A recent study has identified an RNA aptamer that binds to RIG-I, activates signaling, and blocks viral replication in infected host cells, demonstrating potential as an antiviral agent245 and possibly also as an anticancer drug.
8. Perspective
RNA helicases are ubiquitous enzymes that play a central role in RNA metabolism. Genome-wide searches and expression profiling and functional studies have discovered a multitude of RNA helicases, and linked many of these enzymes to various diseases, such as viral and other infections, neurodegenerative and rheumatic disorders, cancer and aging. Although their exact function in the etiology of these diseases is often ill-defined, RNA helicases have proven to constitute promising targets for antiviral and anticancer therapies. Conceivable inhibitory mechanisms include inhibition of the ATPase activity, interference with RNA binding, inhibition of coupling between ATP hydrolysis and RNA unwinding, or inhibition of the RNA translocation activity. Recent advances in understanding the molecular details of RNA helicase mechanisms open up novel avenues for drug design and mechanism-based inhibition. From these studies, general features shared by all enzymes and specific features of individual helicases are beginning to emerge, ultimately allowing to selectively target a single helicase. A novel and promising route to inhibit RNA helicases is to interfere with their conformational changes in the catalytic cycle, and the regulation of the catalytic cycle by auxiliary factors. High throughput screening for inhibitory compounds requires powerful assays. Fluorescence-based assays, particularly those employing FRET, are ideally suited to search for lead compounds that target conformational transitions. Conformation-specific drugs hold great promise for the development of novel classes of potent RNA helicase inhibitors in the future.
| RNA helicase | Disease | Role | references | |
|---|---|---|---|---|
| Viral infections | NS3 helicases | viral infection | RNA virus replication assembly of virus particles | 32 34 |
| NPH-II | vaccinia virus infection | vaccinia virus replication transcription of viral genes | 48 49 | |
| DDX1 | HIV-1, HCV-, polyoma virus-, coronavirus infection | Rev interaction partner Rev oligomerization Rev-mediated nuclear export of HIV-1 transcripts | 58 59 60 | |
| DDX3 | HIV-1 infection | Rev-mediated nuclear export of HIV-1 transcripts | 64 | |
| DDX5/p68 | HIV infection | Rev binding partner Virion assembly Splicing Transcript localization | 65 | |
| DDX6 | HIV-1-, HCV infection | Genome encapsulation Viral replication | 80 79,81 | |
| DDX17 | HIV-1 infection | Rev binding partner Virion assembly Splicing Transcript localization | 65 | |
| DDX21 | HIV-1 infection | Splicing Transcript localization | 65 | |
| DDX24 | HIV-1 infection | HIV-1 Gag and Rev binding partner RNA trafficking for genome packaging | 65 82 | |
| DDX47 | HIV-1 infection | Rev binding partner | 65 | |
| DHX9/RHA | Retrovirus-, adenovirus-, flavovirus infection | Retroviral replication, Gag and Rev binding partner Regulation of transcription nuclear export of unspliced transcripts | 31 65,71 67 72 | |
| DHX36 | HIV-1 infection | Rev binding partner | 65 | |
| RIG-I like receptors | viral infections | Sensors for viral RNAs Innate antiviral immune response | 92 | |
| Protozoic, bacterial and fungal infections | HelTc | Chagas disease | T. cruzi life cycle | 116 |
| DeaD | Chronic gastritis Gastric ulcers | H. pylori life cycle | 118 | |
| HrpA | Lyme disease | B. burgdorferi life cycle | 120 | |
| Vad1 | Cryptococcosis | C. neoformans life cycle | 121 | |
| Neurological disorders | Senataxin | Amyotrophic lateral sclerosis Ataxia-oculomotor apraxia | unknown | 127,128 |
| Gemin3 | Spinal muscular atrophy | snRNP assembly transcription | 135,136 134 | |
| DDX6 | Spinocerebellar ataxia | mRNA decay P body assembly | 122 78 | |
| UAP56 | Alzheimer disease | Spliceosome assembly nuclear export of mRNAs | 139 139 | |
| DDX19 | Lethal congenital contracture syndrome | nuclear export of mRNA s | 144 | |
| Cancer and aging | DDX1 | Neuroblastoma Retinoblastoma | Transcription mRNA processing Translation | 53,54 55,56 57 |
| DDX5/p68 | Colorectal cancer Prostate cancer Breast cancer | miRNA processing and maturation | 146 | |
| DDX39 | Lung cancer Gastrointestinal cancer | Associated with growth Maintenance of genome integrity | 151 152 | |
| eIF4A | Melanoma Liver, lung, colon and breast cancer | Translation initiation | 159 | |
| DHX36 | Aging Cancer | Telomere maintenance mRNA degradation | 174,175 173 | |
| others | Gu | Gastric antral vascular ectasia | Pre-mRNA splicing Translation Growth and development | 182 |
| MDA-5 | Clinically amylopathic dermatomyositis | innate antiviral immune response cellular growth suppression apoptosis | 84 84,99 | |
| DHX9/RHA | Systemic lupus erythematodes | Transcription Translation | 67,190 73 | |
| GRTH/DDX25 | Azoospermia Oligospermia | Posttranscriptional regulator of germ cell development Nuclear mRNA export Regulation of translation | 194 199 | |
| Brr2 | Retinitis pigmentosa | mRNA splicing | 200 |
Acknowledgments
Work in the authors´ laboratory was funded by the Volkswagen Foundation and the Swiss National Science Foundation. We thank Markus Rudolph for critical comments on the manuscript.
| Abbreviations: | |
| AD | alzheimer disease |
| ALS | amyotrophic lateral sclerosis |
| AOA2 | ataxia-oculomotor apraxia type-2 |
| C-ADM | amyopathic dermatomyositis |
| CARD | caspase recruitment domain |
| DENV | dengue virus |
| DM | dermatomyositis |
| FMDV | foot-and-mouth-disease virus |
| H1 | helicase core domain I |
| H2 | helicase core domain II |
| HA2 | helicase associated domain |
| HCV | hepatitis C virus |
| ILD | interstitial lung disease |
| JEV | japanese encephalitis virus |
| KUNV | kunjin virus |
| LCCS | lethal congenital contracture syndrome |
| MEV | murray valley encephalitis virus |
| NPH-II | nucleoside triphosphate phosphohydrolase-II |
| OB/NTD | oligonucleotide/oligosaccharide-binding domain |
| RBD | RNA binding domain |
| RD | regulatory domain |
| RHA | RNA helicase A |
| RNP | ribonucleoprotein complex |
| RRE | rev-responsive element |
| SF | superfamily |
| SLE | systemic lupus erythematodes |
| SMA | spinal muscular atrophy |
| SMN | survival motor neuron |
| SPRY | protein-protein interaction domain (domain in SPla and the RYanodine receptor) |
| YFV | yellow fever virus |
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