Elsevier

Seminars in Immunology

Volume 21, Issue 4, August 2009, Pages 215-222
Seminars in Immunology

Review
RIG-I-like receptors: Sensing and responding to RNA virus infection

https://doi.org/10.1016/j.smim.2009.05.001Get rights and content

Abstract

Viral and microbial pathogens contain specific motifs or pathogen-associated molecular patterns (PAMPs) that are recognized by cell surface- and endosome-associated Toll-like receptors (TLRs). RNA virus infection is also detected through TLR-independent mechanisms. Early viral replicative intermediates are detected by two recently characterized cystolic viral RNA receptors—RIG-I and MDA-5. Both are DExDH/box RNA helicases, and RIG-I specifically recognizes 5′-triphosphate containing viral RNA and transmits signals that induce type I interferon-mediated host immunity against virus infection. In this review, we will focus on RIG-I-like receptor (RLR) signal transduction and the regulatory mechanisms – ubiquitination, deubiquitination, ISGylation – underlying this important host response.

Introduction

The past decade has witnessed tremendous progress in our understanding of the innate host response to infection and the pattern recognition receptors (PRRs) that sense and respond to infectious pathogens. Three major classes of PRRs are involved in the detection of invading pathogens: nucleotide-oligomerization domain (NOD)-like receptors, Toll-like receptors (TLRs), and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) [1], [2], [3]. These sensors are part of a first line of immune defense that sense exogenous pathogens via pathogen-associated molecular patterns (PAMPs), leading to the production of pro-inflammatory cytokines and type I interferons (IFNs). Type I IFN production provokes swift eradication of invading pathogens by stimulating both antiviral immunity and triggering adaptive immunity.

TLRs are transmembrane proteins implicated in the detection of a vast range of microbial pathogens including viruses, bacteria, protozoa, and fungi. TLR signaling is achieved by the recognition of specific PAMPs via extracellular leucine-rich repeat (LRR) motifs that transmit signals through the cytoplasmic Toll-interleukin (IL)-1 receptor (TIR) domain [4], [5]. Among the TLR family, a subgroup of endosome localized TLRs (TLR3, 7, 8, 9) detect nucleic acids particularly viral DNA/RNA and can be distinguished from surface expressed TLRs (TLR1, 2, 4, 5, 6, 10) that recognize bacterial and fungal cell wall components, as well as some viral proteins [6]. TLR3 is known to detect double-stranded (ds) RNA, while TLR7 and TLR8 recognize single-stranded (ss) RNA and TLR9 recognizes unmethylated DNA with CpG motifs [7], [8], [9], [10]. Endosomal TLRs, upon binding to their respective ligands, recruit downstream adaptor molecules such as MyD88 and TIR domain-containing adaptor inducing IFN-β (TRIF) leading to NF-κB and IFN activation [11]. Among the cytoplasmic PRRs, NLRs are known to detect cytosolic microbial components and “danger” signals (such as ATP and toxins) through their characteristic C-terminal LRR and internal nucleotide-binding domain (NBD), leading to the activation of the inflammasome, a large multiprotein complex whose assembly activates caspase-1, promoting the maturation of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 [1], [12].

Recently, several groups have identified another cytoplasmic sensor, the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) as the key sensor for cytoplasmic dsDNA [13], [14], [15], [16]. Cytoplasmic DNA triggers formation of the AIM2 inflammasome by inducing AIM2 oligomerization, leading to activation of the (apoptosis-associated speck-like protein containing a CARD) ASC pyroptosome and caspase-1 [14].

Distinct from the TLR pathways, RIG-I-like receptors (RLRs) – the retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene-5 (MDA-5) – are novel cytoplasmic RNA helicases that recognize viral RNA present within the cytoplasm. Although both TLR7 and TLR9 are critical for recognition of viral nucleic acids in the endosomes of plasmacytoid dendritic cells (pDCs), most other cell types recognize viral RNA intermediates through the RLR arm of the innate immune response [17], [18], [19]. This review will focus on how RLRs detect viral RNA, discriminate between exogenous viral and endogenous self-RNA, and how the host regulates the antiviral response by modulation of RLR-mediated signaling.

Section snippets

Recognition of RNA viruses by RLRs

RIG-I and MDA-5 are closely related proteins that belong to the DExD/H box RNA helicase family and contain two amino (N)-terminal caspase recruitment domains (CARDs), a central ATPase and helicase domain and a carboxy C-terminal regulatory domain [17] (Fig. 1). The importance of the RIG-I pathway in antiviral immunity was confirmed with the generation of RIG-I-deficient mice [20], revealing that RIG-I and not the TLR system played an essential role in the IFN antiviral response in most cell

Molecular structure of RIG-I

RIG-I protein is present in the cytoplasm in an inactive form and is activated by viral infection or transfection of dsRNA. A mutant of RIG-I containing only the N-terminal CARD domain functions as a constitutive activator that induces IFN production in the absence of viral infection, whereas a CARD-deficient mutant of RIG-I functions as a dominant negative inhibitor [17], [35]. Mutagenesis of the adenosine triphosphate (ATP)-binding residue of the helicase domain from lysine to alanine (K270A)

RLR family members MDA-5 and LGP2

Structurally, MDA-5 shows a 23% aa homology to N-terminal tandem CARD domains of RIG-I and a 35% aa homology to the helicase domain of RIG-I (Fig. 1). In contrast, the C-terminal end of MDA-5 does not contain a RD and shows no autoinhibitory function [18], [36]. As mentioned previously, generation of RIG-I and MDA-5 knockout mice demonstrated that these sensors detect different viruses [20], [21]. In addition, a genome-wide association study of nonsynonymous SNPs identified MDA-5 as a gene

RIG-I signal transduction through the mitochondrial MAVS adaptor

The adaptor molecule that provides a link between RIG-I sensing of incoming viral RNA and downstream activation events was independently elucidated as mitochondrial antiviral signaling adaptor (MAVS), also known as (IPS-1/VISA/Cardif) [38], [39], [40], [41]. MAVS consists of an amino-terminal CARD domain, a proline-rich region (PRR) in the middle of the protein, and a C-terminal transmembrane domain (TM) that localized MAVS to the mitochondrial membrane, suggesting a critical function for the

TRAF3

The activation of RIG-I/MDA-5 ultimately leads to the TM-dependent dimerization of the MAVS N-terminal CARD domains, thereby providing an interface for direct binding to and activation of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family members that are involved in both the IFN and NF-κB arms of the innate immune response [56], [57]. MAVS regulation of type I IFN induction is achieved by direct and specific interaction between the TRAF domain of TRAF3 and a

Regulation of RLR signaling by ubiquitination

Activation of RLRs results in the dissemination of an antiviral cascade necessary to combat invading pathogens [76]. Thus, limiting the intensity and duration RLR signaling is essential to prevent this protective response from causing injury to the host. Recent studies have highlighted the importance of ubiquitination in modulating the innate immune response in response to invading pathogens in both the TLR and RLR signaling pathways. TRIM25α, a member of the tripartite motif (TRIM) protein

Conclusions and perspectives

Studies in this rapidly moving field over the past 5 years have defined a dynamic cystolic recognition pathway that triggers a robust innate immune response against RNA virus infection. Also emerging as rapidly are details of the strategies used by different viruses to thwart these defense mechanisms. Many questions still remain unanswered: what are the molecular structures of RNAs recognized by MDA-5; how does RLR signaling access viral ribonucleoprotein complexes following infection; what is

Acknowledgements

This research was supported by grants from Canadian Institutes of Health Research, the National Cancer Institute of Canada, with the support of the Canadian Cancer Society and CANFAR, the Canadian Foundation for AIDS Research. JH was supported by a CIHR Senior Investigator award and PN by a Doctoral Fellowship from FRSQ.

References (90)

  • L.G. Xu et al.

    VISA is an adapter protein required for virus-triggered IFN-beta signaling

    Mol Cell

    (2005)
  • S. Cui et al.

    The C-terminal regulatory domain is the RNA 5′-triphosphate sensor of RIG-I

    Mol Cell

    (2008)
  • D. Bamming et al.

    Regulation of signal transduction by enzymatically inactive antiviral RNA helicase proteins MDA5, RIG-I and LGP2

    J Biol Chem

    (2009)
  • J. Hiscott et al.

    MasterCARD: a priceless link to innate immunity

    Trends Mol Med

    (2006)
  • Q. Sun et al.

    The specific and essential role of MAVS in antiviral innate immune responses

    Immunity

    (2006)
  • R. Yoshida et al.

    TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway

    J Biol Chem

    (2008)
  • S.S. Mikkelsen et al.

    RIG-I-mediated activation of P38 MAPK is essential for viral induction of IFN and activation of dendritic cells: dependence on TRAF2 and TAK1

    J Biol Chem

    (2009)
  • B. Guo et al.

    Modulation of the interferon antiviral response by the TBK1/IKKi adaptor protein TANK

    J Biol Chem

    (2007)
  • M.C. Michallet et al.

    TRADD protein is an essential component of the RIG-like helicase antiviral pathway

    Immunity

    (2008)
  • B. Zhong et al.

    The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation

    Immunity

    (2008)
  • J. Hiscott

    Convergence of the NF-kappaB and IRF pathways in the regulation of the innate antiviral response

    Cytokine Growth Factor Rev

    (2007)
  • H. Oshiumi et al.

    Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-beta induction during the early phase of viral infection

    J Biol Chem

    (2009)
  • K. Arimoto et al.

    UbcH8 regulates ubiquitin and ISG15 conjugation to RIG-I

    Mol Immunol

    (2008)
  • Y.Y. Wang et al.

    A20 is a potent inhibitor of TLR3- and Sendai virus-induced activation of NF-kappaB and ISRE and IFN-beta promoter

    FEBS Lett

    (2004)
  • M. Zhang et al.

    Regulation of IKK-related kinases and antiviral responses by tumor suppressor CYLD

    J Biol Chem

    (2008)
  • J.P. Ting et al.

    NLRs at the intersection of cell death and immunity

    Nat Rev Immunol

    (2008)
  • T. Kawai et al.

    SnapShot: pattern-recognition receptors

    Cell

    (2007)
  • L.A. O’Neill

    The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress

    Immunol Rev

    (2008)
  • M. Gilliet et al.

    Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases

    Nat Rev Immunol

    (2008)
  • T. Kawai et al.

    Toll-like receptor and RIG-I-like receptor signaling

    Ann N Y Acad Sci

    (2008)
  • F. Martinon et al.

    Inflammatory caspases and inflammasomes: master switches of inflammation

    Cell Death Differ

    (2007)
  • V. Hornung et al.

    AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC

    Nature

    (2009)
  • T. Fernandes-Alnemri et al.

    AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA

    Nature

    (2009)
  • T. Burckstummer et al.

    An orthogonal proteomic–genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome

    Nat Immunol

    (2009)
  • T.L. Roberts et al.

    HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA

    Science

    (2009)
  • M. Yoneyama et al.

    The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses

    Nat Immunol

    (2004)
  • M. Yoneyama et al.

    Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity

    J Immunol

    (2005)
  • J. Andrejeva et al.

    The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter

    Proc Natl Acad Sci USA

    (2004)
  • H. Kato et al.

    Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses

    Nature

    (2006)
  • L. Gitlin et al.

    Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus

    Proc Natl Acad Sci USA

    (2006)
  • Y.M. Loo et al.

    Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity

    J Virol

    (2008)
  • H. Kato et al.

    Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5

    J Exp Med

    (2008)
  • B.L. Fredericksen et al.

    Establishment and maintenance of the innate antiviral response to West Nile Virus involves both RIG-I and MDA5 signaling through IPS-1

    J Virol

    (2008)
  • V. Hornung et al.

    5′-Triphosphate RNA is the ligand for RIG-I

    Science

    (2006)
  • A. Pichlmair et al.

    RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates

    Science

    (2006)
  • Cited by (0)

    View full text