RACK1 attenuates RLR antiviral signaling by targeting VISA-TRAF complexes.
Virus-induced signaling adaptor (VISA), which mediates the production of type I interferon, is crucial for the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway. Upon viral infection, RIG-I recognizes double-stranded viral RNA and interacts with VISA to mediate antiviral innate immunity. However, the mechanisms underlying RIG/VISA-mediated antiviral regulation remain ... unclear. In this study, we confirmed that receptor for activated C kinase 1 (RACK1) interacts with VISA and attenuates the RIG/VISA-mediated antiviral innate immune signaling pathway. Overexpression of RACK1 inhibited the interferon-? (IFN-?) promoter; interferon-stimulated response element (ISRE); nuclear factor kappa B (NF-?B) activation; and dimerization of interferon regulatory factor 3 (IRF3) mediated by RIG-I, VISA, and TANK-binding kinase 1 (TBK1). A reduction in RACK1 expression level upon small interfering RNA knockdown increased RIG/VISA-mediated antiviral transduction. Additionally, RACK1 disrupted formation of the VISA-tumor necrosis factor receptor-associated factor 2 (TRAF2), VISA-TRAF3, and VISA-TRAF6 complexes during RIG-I/VISA-mediated signal transduction. Additionally, RACK1 enhanced K48-linked ubiquitination of VISA, attenuated its K63-linked ubiquitination, and decreased VISA-mediated antiviral signal transduction. Together, these results indicate that RACK1 interacts with VISA to repress downstream signaling and downregulates virus-induced IFN-? production in the RIG-I/VISA signaling pathway.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Antiviral Agents, DEAD Box Protein 58, Gene Knockdown Techniques, Humans, Interferon-beta, Lysine, Multiprotein Complexes, Neoplasm Proteins, Promoter Regions, Genetic, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Receptors for Activated C Kinase, Sendai virus, Signal Transduction, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Ubiquitination
Adaptor Proteins, Signal Transducing, Antiviral Agents, DEAD Box Protein 58, Gene Knockdown Techniques, Humans, Interferon-beta, Lysine, Multiprotein Complexes, Neoplasm Proteins, Promoter Regions, Genetic, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Receptors for Activated C Kinase, Sendai virus, Signal Transduction, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Ubiquitination
Biochem. Biophys. Res. Commun.
Date: Dec. 15, 2018
PubMed ID: 30527812
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