Chapter 3 : Cytoplasmic Pattern Receptors (RIG-I and MDA-5) and Signaling in Viral Infections

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Cytoplasmic Pattern Receptors (RIG-I and MDA-5) and Signaling in Viral Infections, Page 1 of 2

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This chapter focuses on the roles of retinoic acid-inducible gene I (RIG-I)-like RNA helicases (RLHs) in RNA virus recognition and RLH signaling pathways. It describes the roles of the toll-like receptors (TLRs) system with respect to the relationship between these two virus recognition mechanisms during the course of RNA virus infections in vivo. RIG-I mediated signaling is positively and negatively controlled by ubiquitination of RIG-I. First, the caspase recruitment domains (CARDs) of RIG-I undergo Lys-63-linked ubiquitination by tripartite motif (TRIM) 25, a ubiquitin E3 ligase composed of a RING finger domain, B box/coiled-coil domain, and SPRY domain. In addition to RLHs, TLRs are also important in recognizing virus infections. Innate immediate immune responses are important for mounting acquired immune responses to viral infections. Recently, two different virus infection models have been analyzed to examine the roles of RLHs and TLRs in the activation of acquired immune responses. The contributions of these two melanoma differentiation-associated gene 5 (MDA-5) and TLR3 systems to the activation of T-cell responses have been examined. Recent progress in studies of RLHs and their signaling pathways has revealed that the RLH system is essential for inducing innate immune responses in response to RNA viruses infecting cells. Furthermore, various immune cells cooperate in order to establish optimized antiviral immune responses. Thus, studies monitoring immune responses in vivo could be vital to fully clarify the mechanisms of antiviral immune responses.

Citation: Takeuchi O, Akira S. 2009. Cytoplasmic Pattern Receptors (RIG-I and MDA-5) and Signaling in Viral Infections, p 29-38. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch3
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Figure 1

RLH-mediated recognition of RNA viruses. RIG-I and MDA-5 recognize 5′-triphosphate RNA and dsRNA from RNA viruses and interact with IPS-1. TRAF3 is recruited to IPS-1, and Lys-63-type polyubiquitination, which is controlled by the presence of DUBA, is induced. Subsequently, TRAF3 recruits TANK/NAP1/SINTBAD and TBK1/IKK-, which phosphorylate IRF3/IRF7. The phosphorylated IRFs translocate into the nucleus and induce the expression of type I IFN genes. NF-κB is also activated by IPS-1 via the FADD and caspase-8/10-dependent pathway.

Citation: Takeuchi O, Akira S. 2009. Cytoplasmic Pattern Receptors (RIG-I and MDA-5) and Signaling in Viral Infections, p 29-38. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch3
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Figure 2

TLR signaling pathways leading to the production of type I IFNs. TLR3 and TLR7/9 activate distinct intracellular signaling pathways. TLR3 recruits TRIF as an adaptor molecule. TRIF associates with TRAF3, TRAF6, and RIP-1, which are responsible for the activation of IRF3, IRF7, and NF-κB. Downstream of TRAF3, TLR3 and RLHs share a common signaling cascade. On the other hand, TLR7 and TLR9 activate specialized signaling cascades in pDCs. In response to RNA and DNA viruses, TLR7 and TLR9 recruit MyD88 as an adaptor and activate IRAK-4, IRAK-1, and TRAF6, resulting in activation of the IKK complex and nuclear translocation of NF-κB, which in turn initiates the expression of proinflammatory cytokine genes. IRAK-1 and IKK-α activate IRF7 together with TRAF3 and IKK-α, and induce nuclear translocation of IRF7. Finally, transcription of type I IFN genes occurs.

Citation: Takeuchi O, Akira S. 2009. Cytoplasmic Pattern Receptors (RIG-I and MDA-5) and Signaling in Viral Infections, p 29-38. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch3
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