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

Abstract

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.

Estrogen receptor alpha inhibits RLR-mediated immune response via ubiquitinating TRAF3

“…Ubiquitination is one of the most versatile posttranslational modifications and plays critical roles in modulating antiviral response properly [35,36]. Posttranslational modification of TRAF3 by K63-linked and K48-linked ubiquitination has been found to maintain its activity in a suitable state after viral stimulation [37,38]. To achieve its negative regulatory function in cellular antiviral response, ERα associates with TRAF3 and promotes K48-linked ubiquitination and degradation.…”

Ubiquitination in the antiviral immune response

“…This interaction activates TBK1/IKKε to phosphorylate IRF3 and IRF7, inducing the transcription of IGSs. The importance of K63-linked ubiquitination for TRAF3-dependent signaling was strengthened by the identification of several DUBs removing the K63-linked ubiquitination from TRAF3: the deubiquitinating enzyme A (DUBA), OTUB1, as well as the ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) that is specifically subverted by high-risk human papillomaviruses to downregulate IRF3 activation and PRR responses [146, 149-151]. Furthermore, OTUD7B (OTU domain-containing protein 7B) was recently shown to interact with TRAF3, removing its K63-linked ubiquitination, which prevented TRAF3 proteolysis and consequently aberrant non-canonical NF-κB activation [152].…”

Genome-wide Analysis of Host-Plasmodium yoelii Interactions Reveals Regulators of the Type I Interferon Response

“…For example, an early increase (24 h) in type I interferon (IFN-I) has been shown to be associated with control of some rodent malaria infections (Liehl et al, 2014; Miller et al, 2014; Wu et al, 2014), but the level of IFN-I declines quickly(Wu et al, 2014), suggesting activation of negative regulators of IFN-I. Various IFN-I regulators have been identified (Pan et al, 2014; Peng et al, 2014), but many more are likely unknown, particularly those that are activated during infections involving complex eukaryotic organisms.…”