ECSIT Bridges RIG-I-Like Receptors to VISA in Signaling Events of Innate Antiviral Responses

Abstract

Upon binding to RNA structures from invading viruses, RIG-I and MDA5 are recruited to mitochondria to interact with VISA and initiate antiviral type I interferon (IFN) responses. How this process is mediated is less understood. In this report, we demonstrate that ECSIT is an essential scaffolding protein that mediates the association of VISA and RIG-I or MDA5. Overexpression of ECSIT potentiated virus-triggered activation of IFN-regulatory factor 3 (IRF3) and expression of IFNB1, whereas knockdown of ECSIT impaired viral infection-induced activation of IRF3 and expression of IFNB1 as well as cellular antiviral responses. Mechanistically, ECSIT was associated with VISA on mitochondria and important for bridging RIG-I and MDA5 to VISA. Our findings suggest that ECSIT mediates virus-triggered type I IFN induction by bridging RIG-I and MDA5 to the VISA complex, and provide new insights into the molecular events of innate antiviral immune responses.

Krüppel-like factor 4 negatively regulates cellular antiviral immune response

“…7 The binding of the C-terminal RNA helicase domain of RIG-I to viral RNA results in its conformational change to form a prion-like structure of the N-terminal CARD domains, which recruits the mitochondrial adaptor VISA (also called MAVS, IPS-1, Cardif) and promote the CARD domain of VISA to form prion-like particles which trigger downstream signaling cascades. [8][9][10][11][12][13] A number of proteins have been implicated in mediating TRIF-, MyD88-or VISA-dependent signaling pathways, including TRAFs, MITA, IKKs, TRADD and RIP1. [14][15][16][17][18] Among these components, TRAF2 and TRAF6 facilitate K63-linked polyubiquitination of RIP and NEMO/IKKc, respectively, which causes the activation of NF-kB.…”

On PAMPs and DAMPs

“…Notably, RIG-I-like receptors execute their antiviral activity by recognizing RNA from certain viral species, resulting in the release of interferon-β and other proinflammatory cytokines [3]. This mechanism also involves the translocation of RIG-I to mitochondria, a mechanism critical for the induction of interferon expression [4]. Considering the importance of PRRs with regard to sensing invading pathogens, it is still an open question whether these receptors are able to distinguish between pathogenic bacteria and the normal flora.…”

MSX1 Modulates RLR-Mediated Innate Antiviral Signaling by Facilitating Assembly of TBK1-Associated Complexes

“…The binding of RLR with viral dsRNA induces conformational changes and oligomerization of RLR that activate virus-triggered signaling adaptor (VISA, also known as MAVS, IPS-1, and Cardif) on the mitochondrial and peroxisomal membranes. VISA forms a signalsome by recruiting and activating multiple signaling components, including WDR5, MITA (also known as STING), TAK1, TBK1, and/or IKKε kinases, leading to activation of transcription factors IFN regulatory factor (IRF)3 and NF-kB and induction of type I IFNs (IFN-a and IFN-b) and inflammatory cytokines (1)(2)(3)(4)(5)(6)(7)(8)(9). Type I IFNs further activate the JAK-STAT signal transduction pathways, leading to transcriptional induction of a wide range of downstream antiviral genes.…”