Abstract
Upon viral infection, retinoic acid–inducible gene I–like receptors (RLRs) recognize viral RNA and trigger a series of signaling events, leading to the induction of type I interferons (IFNs). These processes are delicately regulated to prevent excessive and harmful immune responses. In this study, we identified G patch domain-containing protein 3 (GPATCH3) as a negative regulator of RLR-mediated antiviral signaling pathways. Overexpression of GPATCH3 impaired RNA virus- triggered induction of downstream antiviral genes, whereas its knockdown had opposite effects and attenuated viral replication. In addition, GPATCH3-deficient cells had higher IFNB1 mRNA level compared with control cells after RNA virus infection. Mechanistically, GPATCH3 was recruited to VISA in a viral infection dependent manner and the assembly of VISA/TRAF6/TBK1 signalosome was impaired in GPATCH3-overexpressing cells. In contrast, upon viral infection, the recruitment of TRAF6 and TBK1 to VISA was enhanced in GPATCH3 deficient cells. Taking together, our findings demonstrate that GPATCH3 interacts with VISA and disrupts the assembly of virus-induced VISA signalosome therefore acts as a negative regulator of RLR-mediated innate antiviral immune responses.
Highlights
Recognition of conserved molecular structures of viruses by the host pattern-recognition receptors (PRRs) initiates innate antiviral immune responses
We further found that G patch domain-containing protein 3 (GPATCH3), a functionally uncharacterized protein, interacted with mitochondria-localized VISA upon virus infection and disrupted the assembly of VISA-signalosome
GPATCH3 acts as a negative regulator of VISA and functions as a brake of RIG-like receptors (RLRs)-mediated antiviral innate responses
Summary
Recognition of conserved molecular structures of viruses by the host pattern-recognition receptors (PRRs) initiates innate antiviral immune responses. The binding of RLRs to viral RNAs leads to rapid activation of transcription factors IRF3 and NF-κB, which collaborate to induce transcription of type I interferon (IFN) genes. Type I IFNs activates JAK-STAT signaling pathways to induce the transcription of a wide range of interferon stimulated genes (ISGs) leading to innate antiviral responses [6]. VISA recruits the TRAF proteins through its TRAF-binding motifs [7, 9, 15, 16], which in turn recruit TBK1 and IKKs to the VISA-associated signalosome, in which TBK1 and IKKs phosphorylate IRF3 and NF-κB, respectively leading to the induction of type I IFNs and proinflammatory cytokines [12, 13]. Peroxisomal VISA rapidly mounts a short-term protection by initiating the production of type III IFNs [18]
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