Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: Key regulators of innate immunity

Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 08/2009; 124(2):219-34. DOI: 10.1016/j.pharmthera.2009.06.012
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The innate immune system responds within minutes of infection to produce type I interferons and pro-inflammatory cytokines. Interferons induce the synthesis of cell proteins with antiviral activity, and also shape the adaptive immune response by priming T cells. Despite the discovery of interferons over 50 years ago, only recently have we begun to understand how cells sense the presence of a virus infection. Two families of pattern recognition receptors have been shown to distinguish unique molecules present in pathogens, such as bacterial and fungal cell wall components, viral RNA and DNA, and lipoproteins. The first family includes the membrane-bound toll-like receptors (TLRs). Studies of the signaling pathways that lead from pattern recognition to cytokine induction have revealed extensive and overlapping cascades that involve protein-protein interactions and phosphorylation, and culminate in activation of transcription proteins that control the transcription of genes encoding interferons and other cytokines. A second family of pattern recognition receptors has recently been identified, which comprises the cytoplasmic sensors of viral nucleic acids, including MDA-5, RIG-I, and LGP2. In this review we summarize the discovery of these cytoplasmic sensors, how they recognize nucleic acids, the signaling pathways leading to cytokine synthesis, and viral countermeasures that have evolved to antagonize the functions of these proteins. We also consider the function of these cytoplasmic sensors in apoptosis, development and differentiation, and diabetes.

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    • "RIG-I specifically detects the intracellular double-stranded viral RNA bearing 5′ triphosphate and panhandle structures to activate antiviral signaling (Hornung et al., 2006; Pichlmair et al., 2006). Once a host is invaded by a virus, PRRs transmit signals to the downstream kinases that activate transcription factors, including IFN regulatory factor-3 (IRF3), nuclear factor κB (NF-κB), and ATF-2/c-jun, with the help of different adaptor molecules (MAVS/IPS-1/VISA/Cardif for RIG-I, TRIF for TLR3, and MyD88 for TLR7/8/9) to activate IFN production (Barral et al., 2009; Yoneyama and Fujita, 2009; Chen and Jiang, 2013). A previous study suggested that TRAF family members are involved in the regulation of inflammation and antiviral responses (Saha and Cheng, 2006). "
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    ABSTRACT: SARS coronavirus (SARS-CoV) develops an antagonistic mechanism by which to evade the antiviral activities of interferon (IFN). Previous studies suggested that SARS-CoV papain-like protease (PLpro) inhibits activation of the IRF3 pathway, which would normally elicit a robust IFN response, but the mechanism(s) used by SARS PLpro to inhibit activation of the IRF3 pathway is not fully known. In this study, we uncovered a novel mechanism that may explain how SARS PLpro efficiently inhibits activation of the IRF3 pathway. We found that expression of the membrane-anchored PLpro domain (PLpro-TM) from SARS-CoV inhibits STING/TBK1/IKKε-mediated activation of type I IFNs and disrupts the phosphorylation and dimerization of IRF3, which are activated by STING and TBK1. Meanwhile, we showed that PLpro-TM physically interacts with TRAF3, TBK1, IKKε, STING, and IRF3, the key components that assemble the STING-TRAF3-TBK1 complex for activation of IFN expression. However, the interaction between the components in STING-TRAF3-TBK1 complex is disrupted by PLpro-TM. Furthermore, SARS PLpro-TM reduces the levels of ubiquitinated forms of RIG-I, STING, TRAF3, TBK1, and IRF3 in the STING-TRAF3-TBK1 complex. These results collectively point to a new mechanism used by SARS-CoV through which PLpro negatively regulates IRF3 activation by interaction with STING-TRAF3-TBK1 complex, yielding a SARS-CoV countermeasure against host innate immunity.
    Protein & Cell 03/2014; 5(5). DOI:10.1007/s13238-014-0026-3 · 3.25 Impact Factor
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    • "Komórki układu odpornościowego rozpoznają za pośrednictwem RIG-I oraz MDA5 niezmodyfikowane cząsteczki wirusowego ssRNA i dsRNA, które w warunkach naturalnych nie są syntetyzowane w komórkach gospodarza [5] [39] (tabela 1). Istnienie grup fosforanowych na końcu 5' jest cechą wirusowych i komórkowych cząsteczek ssRNA. "
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    ABSTRACT: The innate nonspecific immunity is the first line of defense against viral infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are two main receptor families detecting viral nucleic acid. So far, three RLR family members were characterized: RIG-I, MDA5 and LGP2. RLR constitute a family of cytoplasmic helicases, which recognized intracellular single-stranded and double-stranded RNA that is introduced to cytosol during viral infection and replication. In this work we review the current knowledge about the mechanisms of viral recognition by RIG-I-like receptors and their signaling pathways for the activation of type I interferons and pro-inflammatory cytokines synthesis.
    Postępy Higieny i Medycyny Doświadczalnej (Advances in Hygiene and Experimental Medicine) 01/2014; 68:541-56. DOI:10.5604/17322693.1102281 · 0.57 Impact Factor
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    • "Viral infections are characteristically accompanied by type I interferon responses resulting from interaction of viral RNA with TLR7 and TLR3, for respectively single- stranded RNA or double-stranded RNA getting access to endosomal compartments [7]. In addition, cytoplasmic RNA helicase-like sensors such as RIG-I and MDA detect viral RNA upon infection when viral RNA replication intermediates are present in the cytoplasm [8–11]. Type I interferon induction is a crucial step to initiate the cellular antiviral response, but in addition affects the nature and efficacy of the induction of adaptive immune responses [12]. "
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    ABSTRACT: Innate immune responses elicited upon virus exposure are crucial for the effective eradication of viruses, the onset of adaptive immune responses and for establishing proper immune memory. Respiratory syncytial virus (RSV) is responsible for a high disease burden in neonates and immune compromised individuals, causing severe lower respiratory tract infections. During primary infections exuberant innate immune responses may contribute to disease severity. Furthermore, immune memory is often insufficient to protect during RSV re-exposure, which results in frequent symptomatic reinfections. Therefore, identifying the cell types and pattern recognition receptors (PRRs) involved in RSV-specific innate immune responses is necessary to understand incomplete immunity against RSV. We investigated the innate cellular response triggered upon infection of epithelial cells and peripheral blood mononuclear cells. We show that CD14(+) myeloid cells and epithelial cells are the major source of IL-8 and inflammatory cytokines, IL-6 and TNF-α, when exposed to live RSV Three routes of RSV-induced IFN-α production can be distinguished that depend on the cross-talk of different cell types and the presence or absence of virus specific antibodies, whereby pDC are the ultimate source of IFN-α. RSV-specific antibodies facilitate direct TLR7 access into endosomal compartments, while in the absence of antibodies, infection of monocytes or epithelial cells is necessary to provide an early source of type I interferons, required to engage the IFN-α,β receptor (IFNAR)-mediated pathway of IFN-α production by pDC. However, at high pDC density infection with RSV causes IFN-α production without the need for a second party cell. Our study shows that cellular context and immune status are factors affecting innate immune responses to RSV. These issues should therefore be addressed during the process of vaccine development and other interventions for RSV disease.
    PLoS ONE 11/2013; 8(11):e81695. DOI:10.1371/journal.pone.0081695 · 3.23 Impact Factor
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