HSCARG Negatively Regulates the Cellular Antiviral RIG-I Like Receptor Signaling Pathway by Inhibiting TRAF3 Ubiquitination via Recruiting OTUB1

PLoS Pathogens

Ruidan Xu¹  Yanyan Peng²  Xiaofeng Zheng² 

[1] Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China;State Key Lab of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China

关键词: Ubiquitination;    Transcription factors;    Interferons;    Phosphorylation;    Luciferase assay;    Viral transmission;    infection;    Small interfering RNAs;    Vesicular stomatitis virus;   

DOI  :  10.1371/journal.ppat.1004041

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

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