ATPase‐driven oligomerization of RIG‐I on RNA allows optimal activation of type‐I interferon

Patel, Jenish; Jain, Ankur; Chou, Yi Ying; Baum, Alina; Ha, Taekjip; Garcı́a-Sastre, Adolfo

doi:10.1038/embor.2013.102

Cited by 114 publications

(128 citation statements)

References 29 publications

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“…NC_018137.1). An expression plasmid carrying green fluorescent protein (GFP)-tagged LC3 (GFP-LC3) (plasmid 21073) was obtained from Addgene (41), and plasmids carrying RIG-I, TRIM25, MAVS, TBK1, interferon regulatory factor 3 (IRF3), constitutively activated IRF3 (IRF3-5D), dominant negative Rab5 (S34N), and the corresponding fusion proteins were previously described (42)(43)(44) or constructed following standard cloning procedures. Plasmids carrying red fluorescent protein (RFP)-tagged B4GalT1 (B4GalT1-RFP), TGOLN-RFP, CALR-C-RFP, Rab5-RFP, and Rab4-RFP were obtained from OriGene.…”

Section: Methodsmentioning

confidence: 99%

Hijacking of RIG-I Signaling Proteins into Virus-Induced Cytoplasmic Structures Correlates with the Inhibition of Type I Interferon Responses

Santiago

Covaleda

Sánchez-Aparicio

et al. 2014

J Virol

103

109

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Recognition of viral pathogens by the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family results in the activation of type I interferon (IFN) responses.To avoid this response, most viruses have evolved strategies that target different essential steps in the activation of host innate immunity. In this study, we report that the nonstructural protein NSs of the newly described severe fever with thrombocytopenia syndrome virus (SFTSV) is a potent inhibitor of IFN responses. The SFTSV NSs protein was found to inhibit the activation of the beta interferon (IFN-␤) promoter induced by viral infection and by a RIG-I ligand. Astonishingly, we found that SFTSV NSs interacts with and relocalizes RIG-I, the E3 ubiquitin ligase TRIM25, and TANK-binding kinase 1 (TBK1) into SFTSV NSs-induced cytoplasmic structures. Interestingly, formation of these SFTSV NSs-induced structures occurred in the absence of the Atg7 gene, a gene essential for autophagy. Furthermore, confocal microscopy studies revealed that these SFTSV NSs-induced structures colocalize with Rab5 but not with Golgi apparatus or endoplasmic reticulum markers. Altogether, the data suggest that sequestration of RIG-I signaling molecules into endosome-like structures may be the mechanism used by SFTSV to inhibit IFN responses and point toward a novel mechanism for the suppression of IFN responses. IMPORTANCEThe mechanism by which the newly described SFTSV inhibits host antiviral responses has not yet been fully characterized. In this study, we describe the redistribution of RIG-I signaling components into virus-induced cytoplasmic structures in cells infected with SFTSV. This redistribution correlates with the inhibition of host antiviral responses. Further characterization of the interplay between the viral protein and components of the IFN responses could potentially provide targets for the rational development of therapeutic interventions.

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Section: Methodsmentioning

confidence: 99%

Hijacking of RIG-I Signaling Proteins into Virus-Induced Cytoplasmic Structures Correlates with the Inhibition of Type I Interferon Responses

Santiago

Covaleda

Sánchez-Aparicio

et al. 2014

J Virol

103

109

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“…An interpretation of this repetitive intra-molecular motion is that RIG-I may be able to translocate along duplex RNA, 34 allowing multiple copies of RIG-I to assemble and reside on a single duplex RNA to provide stronger stimulatory signals for IFN production. [34][35][36] However, several conflicting reports related to this proposed mechanism of RIG-I signaling still need to be reconciled. First, in order for RIG-I to translocate along RNA duplex, the CTD must no longer cap the RNA end and the high-affinity interaction between the CTD and the triphosphates must be disrupted.…”

Section: Rig-i Prefers Capping the Ends Of Rna Duplex Rather Than Binmentioning

confidence: 99%

“…30 Interestingly, new evidence from EM studies in the Hur lab suggests that, despite the lack of cooperativity, internal binding could be induced by a nucleation effect initiated by RIG-I capping at the end of the RNA duplex, which could lead to a more robust interferon response. 35,36 Conceivably, at lower concentrations of RIG-I in the resting state, RIG-I surveys and binds only the ends of 5′trisphor-phylated RNA, but upon IFN induction and the concomitant increase in cellular levels of RIG-I protein, RIG-I molecules may start to bind internally near the RIG-I-capped RNA. 35,37 A distinct conformation of RIG-I bound internally to the duplex RNA is therefore highly desirable, which may provide a second-similar but not identical-means to activate RIG-I.…”

Section: Rig-i Prefers Capping the Ends Of Rna Duplex Rather Than Binmentioning

confidence: 99%

“…35,36 Conceivably, at lower concentrations of RIG-I in the resting state, RIG-I surveys and binds only the ends of 5′trisphor-phylated RNA, but upon IFN induction and the concomitant increase in cellular levels of RIG-I protein, RIG-I molecules may start to bind internally near the RIG-I-capped RNA. 35,37 A distinct conformation of RIG-I bound internally to the duplex RNA is therefore highly desirable, which may provide a second-similar but not identical-means to activate RIG-I. Carefully designed experiments are needed to further clarify the functional implications of this RNA end capping preference vs. the duplex internal binding activity of RIG-I in vivo.…”

Section: Rig-i Prefers Capping the Ends Of Rna Duplex Rather Than Binmentioning

confidence: 99%

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Toward a crystal-clear view of the viral RNA sensing and response by RIG-I-like receptors

Luo

2014

RNA Biology

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“…Recent studies on negative-strand RNA viruses spanning Bunyaviridae, Orthomyxoviridae, Paramyxoviridae, and Rhabdoviridae have proposed that the 5=-triphosphate-containing panhandle structure formed from viral RNA (vRNA) is required for RIG-I activation (5,(14)(15)(16)(17). The double-strandedness of the panhandle structure is derived from the self-complementarity of the viral genome extremities (5).…”

mentioning

confidence: 99%

Influenza A Virus Panhandle Structure Is Directly Involved in RIG-I Activation and Interferon Induction

Liu¹,

Park²,

Pyo

et al. 2015

J Virol

101

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Retinoic acid-inducible gene I (RIG-I) is an important innate immune sensor that recognizes viral RNA in the cytoplasm. Its nonself recognition largely depends on the unique RNA structures imposed by viral RNA. The panhandle structure residing in the influenza A virus (IAV) genome, whose primary function is to serve as the viral promoter for transcription and replication, has been proposed to be a RIG-I agonist. However, this has never been proved experimentally. Here, we employed multiple approaches to determine if the IAV panhandle structure is directly involved in RIG-I activation and type I interferon (IFN) induction. First, in porcine alveolar macrophages, we demonstrated that the viral genomic coding region is dispensable for RIG-I-dependent IFN induction. Second, using in vitro-synthesized hairpin RNA, we showed that the IAV panhandle structure could directly bind to RIG-I and stimulate IFN production. Furthermore, we investigated the contributions of the wobble base pairs, mismatch, and unpaired nucleotides within the wild-type panhandle structure to RIG-I activation. Elimination of these destabilizing elements within the panhandle structure promoted RIG-I activation and IFN induction. Given the function of the panhandle structure as the viral promoter, we further monitored the promoter activity of these panhandle variants and found that viral replication was moderately affected, whereas viral transcription was impaired dramatically. In all, our results indicate that the IAV panhandle promoter region adopts a nucleotide composition that is optimal for balanced viral RNA synthesis and suboptimal for RIG-I activation. IMPORTANCEThe IAV genomic panhandle structure has been proposed to be an RIG-I agonist due to its partial complementarity; however, this has not been experimentally confirmed. Here, we provide direct evidence that the IAV panhandle structure is competent in, and sufficient for, RIG-I activation and IFN induction. By constructing panhandle variants with increased complementarity, we demonstrated that the wild-type panhandle structure could be modified to enhance RIG-I activation and IFN induction. These panhandle variants posed moderate influence on viral replication but dramatic impairment of viral transcription. These results indicate that the IAV panhandle promoter region adopts a nucleotide composition to achieve optimal balance of viral RNA synthesis and suboptimal RIG-I activation. Our results highlight the multifunctional role of the IAV panhandle promoter region in the virus life cycle and offer novel insights into the development of antiviral agents aiming to boost RIG-I signaling or virus attenuation by manipulating this conserved region.

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ATPase‐driven oligomerization of RIG‐I on RNA allows optimal activation of type‐I interferon

Cited by 114 publications

References 29 publications

Hijacking of RIG-I Signaling Proteins into Virus-Induced Cytoplasmic Structures Correlates with the Inhibition of Type I Interferon Responses

Hijacking of RIG-I Signaling Proteins into Virus-Induced Cytoplasmic Structures Correlates with the Inhibition of Type I Interferon Responses

Toward a crystal-clear view of the viral RNA sensing and response by RIG-I-like receptors

Influenza A Virus Panhandle Structure Is Directly Involved in RIG-I Activation and Interferon Induction

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