HSCARG negatively regulates the cellular antiviral RIG-I like receptor signaling pathway by inhibiting TRAF3 ubiquitination via recruiting OTUB1.
RIG-I like receptors (RLRs) recognize cytosolic viral RNA and initiate innate immunity; they increase the production of type I interferon (IFN) and the transcription of a series of antiviral genes to protect the host organism. Accurate regulation of the RLR pathway is important for avoiding tissue injury induced by excessive immune response. HSCARG is a newly reported negative regulator of NF-κB. Here we demonstrated that HSCARG participates in innate immunity. HSCARG inhibited the cellular antiviral response in an NF-κB independent manner, whereas deficiency of HSCARG had an opposite effect. After viral infection, HSCARG interacted with tumor necrosis receptor-associated factor 3 (TRAF3) and inhibited its ubiquitination by promoting the recruitment of OTUB1 to TRAF3. Knockout of HSCARG attenuated the de-ubiquitination of TRAF3 by OTUB1, and knockdown of OTUB1 abolished the effect of HSCARG. HSCARG also interacted with Ikappa-B kinase epsilon (IKKε) after viral infection and impaired the association between TRAF3 and IKKε, which further decreased the phosphorylation of IKKε and interferon response factor 3 (IRF3), thus suppressed the dimerization and nuclear translocation of IRF3. Moreover, knockdown of TRAF3 dampened the inhibitory effect of IFN-β transcription by HSCARG, suggesting that TRAF3 is necessary for HSCARG to down-regulate RLR pathway. This study demonstrated that HSCARG is a negative regulator that enables balanced antiviral innate immunity.
State Key Lab of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China.
Yanyan
Y
Peng
State Key Lab of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China.
Ruidan
R
Xu
State Key Lab of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China.
Xiaofeng
X
Zheng
D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000072017:Deubiquitinating Enzymes; D055785:Gene Knockdown Techniques; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D012327:RNA Virus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012328:RNA Viruses / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000502:physiology*; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
C520476:NMRAL1 protein, human; D012367:RNA, Viral; D011971:Receptors, Immunologic; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D014157:Transcription Factors; D051550:I-kappa B Kinase; D000072017:Deubiquitinating Enzymes; C538826:OTUB1 protein, human; D003546:Cysteine Endopeptidases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases