The Structural Basis of 5′ Triphosphate Double-Stranded RNA Recognition by RIG-I C-Terminal Domain

Lü, Cheng; Xu, Hengyu; Ranjith-Kumar, C. T.; Brooks, Monica T.; Hou, Tim Y.; Hu, Fuqu; Herr, Andrew B.; Strong, Roland K.; Kao, C. Cheng; Li, Pingwei

doi:10.1016/j.str.2010.05.007

Cited by 196 publications

(282 citation statements)

References 41 publications

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“…Although the blunt-ended 5Ј OH dsRNAs that we have used have not induced IFN upon transfection into cells, Lu et al (17) have reported that a 27-bp blunt-ended 5Ј OH dsRNA does induce IFN. More importantly, they have found that mutation of one of the four basic residues that directly interacts with the 5Ј ppp (K861E) abolished the ability of 5Ј ppp dsRNA to induce IFN but had virtually no effect on that of the 27-bp blunt-ended 5Ј OH dsRNA.…”

Section: Discussionmentioning

confidence: 81%

“…The high resolution structures of the CTD bound to 5Ј ppp dsRNAs have found that the CTD interacts with dsRNA in large part through extensive electrostatic interactions with the 5Ј ppp group, consistent with the significantly higher affinity of the CTD for 5Ј ppp dsRNAs than for 5Ј OH dsRNAs. Despite the highly electrostatic nature of CTD/ 5Ј ppp dsRNA interactions, both its association and dissociation are relatively slow (17,29). The unique slow dissociation kinetics of this interaction (t1 ⁄ 2 ϭ 327 s), as opposed to that of CTD and 5Ј OH dsRNA (t1 ⁄ 2 ϭ 28s), together with the higher affinity of the 5Ј ppp dsRNA presumably help explain why our 5Ј ppp dsRNA strongly induces IFN, whereas our 5Ј OH dsRNA does not (Fig.…”

Section: Discussionmentioning

confidence: 87%

“…More recently, three crystal structures of the CTD bound to 12-14 bp 5Ј ppp-dsRNAs were determined (16,17). The CTD binds to both ends of the self-complementary 5Ј ppp dsRNAs and contacts the A-form dsRNA primarily through a few nucleotides at the 5Ј-end, with the ␣, ␤, and ␥ 5Ј-phosphates surrounded by multiple lysines and anchored in the basic cleft via electrostatic interactions and multiple H-bonds.…”

mentioning

confidence: 99%

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Short Double-stranded RNAs with an Overhanging 5′ ppp-Nucleotide, as Found in Arenavirus Genomes, Act as RIG-I Decoys

Marq

Hausmann

Veillard

et al. 2011

Journal of Biological Chemistry

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Arenavirus RNA genomes are initiated by a "prime and realign" mechanism, such that the initiating GTP is found as a single unpaired (overhanging) nucleotide when the complementary genome ends anneal to form double-stranded (ds) RNA panhandle structures. dsRNAs modeled on these structures do not induce interferon (IFN), as opposed to bluntended 5 ppp dsRNA. This study examines whether these viral structures can also act as decoys, by trapping RIG-I in inactive dsRNA complexes. We examined the ability of various dsRNAs to activate the RIG-I ATPase (presumably a measure of helicase translocation on dsRNA) relative to their ability to induce IFN. We found that there is no simple relationship between these two properties, as if RIG-I can translocate on short dsRNAs without inducing IFN. Moreover, we found that 5 ppp dsRNAs with a single unpaired 5 ppp-nucleotide can in fact competitively inhibit the ability of blunt-ended 5 ppp dsRNAs to induce IFN when co-transfected into cells and that this inhibition is strongly dependent on the presence of the 5 ppp. In contrast, 5 ppp dsRNAs with a single unpaired 5 ppp-nucleotide does not inhibit poly(I-C)-induced IFN activation, which is independent of the presence of a 5 ppp group.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 99%

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Short Double-stranded RNAs with an Overhanging 5′ ppp-Nucleotide, as Found in Arenavirus Genomes, Act as RIG-I Decoys

Marq

Hausmann

Veillard

et al. 2011

Journal of Biological Chemistry

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“…Previous structural studies showed that a KWK motif in the CTD of RIG-I mediates physical interaction between RIG-I and dsRNA, although it is unknown whether the interaction is functionally important (26,27,37). Because the KWK motif is conserved in DRH-1 CTD (Fig.…”

Section: The Helicase and Ctd Domains Of Rig-i Were Functional In A Fmentioning

confidence: 98%

Homologous RIG-I–like helicase proteins direct RNAi-mediated antiviral immunity in C. elegans by distinct mechanisms

Guo

Zhang

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

128

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RNAi-mediated antiviral immunity in Caenorhabditis elegans requires Dicer-related helicase 1 (DRH-1), which encodes the helicase and C-terminal domains homologous to the mammalian retinoic acid inducible gene I (RIG-I)-like helicase (RLH) family of cytosolic immune receptors. Here we show that the antiviral function of DRH-1 requires the RIG-I homologous domains as well as its wormspecific N-terminal domain. We also demonstrate that the helicase and C-terminal domains encoded by either worm DRH-2 or human RIG-I can functionally replace the corresponding domains of DRH-1 to mediate antiviral RNAi in C. elegans. Notably, substitutions in a three-residue motif of the C-terminal regulatory domain of RIG-I that physically interacts with viral double-stranded RNA abolish the antiviral activity of C-terminal regulatory domains of both RIG-I and DRH-1 in C. elegans. Genetic analysis revealed an essential role for both DRH-1 and DRH-3 in C. elegans antiviral RNAi targeting a natural viral pathogen. However, Northern blot and small RNA deep sequencing analyses indicate that DRH-1 acts to enhance production of viral primary siRNAs, whereas DRH-3 regulates antiviral RNAi by participating in the biogenesis of secondary siRNAs after Dicer-dependent production of primary siRNAs. We propose that DRH-1 facilitates the acquisition of viral double-stranded RNA by the worm dicing complex for the subsequent processing into primary siRNAs. The strong parallel for the antiviral function of RLHs in worms and mammals suggests that detection of viral doublestranded RNA may activate completely unrelated effector mechanisms or, alternatively, that the mammalian RLHs have a conserved activity to stimulate production of viral siRNAs for antiviral immunity by an RNAi effector mechanism.I nnate immunity refers to ancient host defense systems that act immediately after pathogen attack and are under the control of germline-encoded immune receptors. Pathogen sensing by several classes of immune receptors such as retinoic acid inducible gene I (RIG-I)-like cytosolic sensors in mammals leads to the transcriptional activation of effector genes in the nucleus (1). In contrast, detection of viral double-stranded RNA (dsRNA) by Dicer endonucleases is associated with the production of small interfering RNAs (siRNAs), which subsequently direct sequencespecific antiviral immunity through RNA interference (RNAi) (2-5). Antiviral RNAi is a major antiviral defense mechanism in fungi, plants, insects, and nematodes, so that suppression of the defense by a virus-encoded suppressor of RNAi is essential to establish infection (6-8). Although the RNAi machinery is highly conserved in mammals, conclusive evidence for a natural antiviral role of RNAi in mammals is not available (9).The nematode Caenorhabditis elegans has recently emerged as a small-animal model for innate immunity studies (10, 11). Genetic studies indicate that antiviral RNAi in C. elegans requires the genes essential for RNAi induced by exogenous dsRNA (12-17). These include Dicer-1 and dsRNA-bind...

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“…Thus, it was thought that RIG-I recognizes dsRNA replicative intermediates of negative stranded single-stranded RNA (ssRNA) viruses, while MDA5 responds to long dsRNA replicative intermediates of plus strand ssRNA viruses [84][85][86][87]. Indeed, the struc-npg ture of RIG-I bound to short dsRNA products has recently been solved [88,89]. RIG-I has also recently been implicated in the recognition of DNA viruses by binding short dsRNAs generated by RNA polIII [90].…”

Section: Pattern Recognition Receptorsmentioning

confidence: 99%

NF-κB in immunobiology

2011

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NF-κB was first discovered and characterized 25 years ago as a key regulator of inducible gene expression in the immune system. Thus, it is not surprising that the clearest biological role of NF-κB is in the development and function of the immune system. Both innate and adaptive immune responses as well as the development and maintenance of the cells and tissues that comprise the immune system are, at multiple steps, under the control of the NF-κB family of transcription factors. Although this is a well-studied area of NF-κB research, new and significant findings continue to accumulate. This review will focus on these areas of recent progress while also providing a broad overview of the roles of NF-κB in mammalian immunobiology.

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The Structural Basis of 5′ Triphosphate Double-Stranded RNA Recognition by RIG-I C-Terminal Domain

Cited by 196 publications

References 41 publications

Short Double-stranded RNAs with an Overhanging 5′ ppp-Nucleotide, as Found in Arenavirus Genomes, Act as RIG-I Decoys

Short Double-stranded RNAs with an Overhanging 5′ ppp-Nucleotide, as Found in Arenavirus Genomes, Act as RIG-I Decoys

Homologous RIG-I–like helicase proteins direct RNAi-mediated antiviral immunity in C. elegans by distinct mechanisms

NF-κB in immunobiology

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