Incoming RNA Virus Nucleocapsids Containing a 5′-Triphosphorylated Genome Activate RIG-I and Antiviral Signaling

Weber, Michaela; Gawanbacht, Ali; Habjan, Matthias; Rang, Andreas; Borner, Christoph; Schmidt, Anna Mareike; Veitinger, Sophie; Jacob, Ralf; Devignot, Stéphanie; Kochs, Georg; Garcı́a-Sastre, Adolfo; Weber, Friedemann

doi:10.1016/j.chom.2013.01.012

Cited by 167 publications

(178 citation statements)

References 65 publications

(83 reference statements)

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“…Remarkably, a recent study taking advantage of the three-dimensional stochastic optical reconstruction microscopy (STORM) technique clearly visualized an association of RIG-I with incoming IAV vRNP at the mitochondrion (59). This is also in line with a previous report demonstrating that RIG-I recognizes incoming bunyavirus vRNP (16). These results imply that RIG-I is able to capture a certain RNA configuration imposed by the promoter-proximal strands, which is most likely the panhandle configuration.…”

Section: Discussionsupporting

confidence: 87%

“…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).…”

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confidence: 99%

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

Liu¹,

Park²,

Pyo

et al. 2015

J Virol

110

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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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Section: Discussionsupporting

confidence: 87%

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

110

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“…4А, Б, В, Г). Оба вида рецепторов уча-ствуют в узнавании РНК и РНП вируса гриппа А и индуцируют сигнальные реакции антивирус-ного ответа [18,21,32].…”

Section: действие вируса гриппа а (H1n1)pdm09 на экс-прессию генов Cиunclassified

“…В за-раженных GM-Мф длительно присутствовали вирусные РНК -агонисты эндоплазматического TLR7 и цитоплазматического RIG1 рецепторов [18,32]. От активности этих рецепторов во мно-гом зависят антивирусные функции Мф и сте-пень воспалительного ответа [25].…”

Section: взаимодействие вируса гриппа а с макрофагамиunclassified

“…На клеточной мембране рецептор TLR4 и C-тип лектиновых ре-цепторов (MMR-манозный и MGL-галактозный) взаимодействуют с глипопротеинами оболочки -гемагглютинином (ГА) и нейраминидазой (NA) [22]. Внутри клеток эндосомальные рецепторы TLR3, TLR7, TLR10 и цитоплазматический RIG1 реагируют на вирусные РНК и РНП [18,29,32].…”

Section: Introductionunclassified

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IN VITRO INTERACTION OF INFLUENZA VIRUS A(H1N1)pdm09 WITH MONOCYTIC MACROPHAGES: INDIVIDUAL RESPONSES OF TLR7 AND RIG1 RECEPTOR GENES

et al. 2017

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NLRC5 interacts with RIG‐I to induce a robust antiviral response against influenza virus infection

et al. 2014

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The NLR protein, NLRC5 is an important regulator of MHC class I gene expression, however, the role of NLRC5 in other innate immune responses is less well defined. In the present study, we report that NLRC5 binds RIG-I and that this interaction is critical for robust antiviral responses against influenza virus. Overexpression of NLRC5 in the human lung epithelial cell line, A549, and normal human bronchial epithelial cells resulted in impaired replication of influenza virus A/Puerto Rico/8/34 virus (PR8) and enhanced IFN-β expression. Influenza virus leads to induction of IFN-β that drives RIG-I and NLRC5 expression in host cells. Our results suggest that NLRC5 extends and stabilizes influenza virus induced RIG-I expression and delays expression of the viral inhibitor protein NS1. We show that NS1 binds to NLRC5 to suppress its function. Interaction domain mapping revealed that NLRC5 interacts with RIG-I via its N-terminal death domain and that NLRC5 enhanced antiviral activity in an leucine-rich repeat domain independent manner. Taken together, our findings identify a novel role for NLRC5 in RIG-I-mediated antiviral host responses against influenza virus infection, distinguished from the role of NLRC5 in MHC class I gene regulation.Keywords: Influenza r Interferon r NLRC5 r NS1 r RIG-I Antiviral Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe innate immune system relies on pathogen sensors to provide defense against invading pathogens. To detect diverse pathogen-associated molecular patterns (PAMPs), several classes Correspondence: Dr. Priya Ranjan e-mail: pranjan@cdc.gov of pattern-recognition receptors (PRRs) have evolved in mammals including RIG-I-like receptors, Toll-like receptors (TLRs), and nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs) [1][2][3]. Recognition and binding of PRRs to their cognate ligands often result in conformational changes triggering downstream innate immune signaling [4].In recent years, there has been marked progress in our understanding of NLRs as critical regulators of innate and adaptive C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 758-772 Immunity to infection 759 immune responses. Emerging evidence suggests that NLR family members play crucial roles in antiviral responses [5,6]. NLR proteins have a typical tripartite structure: a C-terminal LRR domain that, in most cases, is associated with PAMP sensing, a centrally located nucleotide-triphosphatase (NTPase) (NACHTdomain present in NAIP, CIITA, HET-E, and TP1) domain responsible for self-oligomerization, and an N-terminal effector domain that mediates protein-protein interactions for initiating downstream signaling [5]. Activation of these receptors induces the production of proinflammatory cytokines, in many cases by the formation of high molecular weight complexes called inflammasomes that lead to caspase-1 activation. However, some of the family members such as NL...

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Incoming RNA Virus Nucleocapsids Containing a 5′-Triphosphorylated Genome Activate RIG-I and Antiviral Signaling

Cited by 167 publications

References 65 publications

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

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

IN VITRO INTERACTION OF INFLUENZA VIRUS A(H1N1)pdm09 WITH MONOCYTIC MACROPHAGES: INDIVIDUAL RESPONSES OF TLR7 AND RIG1 RECEPTOR GENES

NLRC5 interacts with RIG‐I to induce a robust antiviral response against influenza virus infection

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