Scavenger receptor A impairs interferon response to HBV infection by limiting TRAF3 ubiquitination through recruiting OTUB1

Abstract

The battle between hepatitis B virus (HBV) infection and the host immune defense determines the outcome of the disease. Scavenger receptor A (SRA) is a phagocytic pattern recognition receptor involved in various cellular processes, including lipid metabolism, recognition, and clearance of pathogens or modified self‐molecules. Emerging evidence pointed out that SRA might act as an immunomodulator that contributes to innate immune defense against invading pathogens. Herein, we examined the role of SRA in the initiation of type I interferon (IFN) response to HBV infection and the virus clearance. Our results showed that SRA‐deficient (SRA−/−) mice were resistant to HBV infection developed by hydrodynamic injection of HBV replicon plasmid. We found lower levels of HBV DNA and viral protein expression in SRA−/− mice, which was associated with enhanced type I IFN production, compared with wild‐type controls. Besides, we performed gain and loss of function experiments and determined that SRA inhibits innate antiviral immune responses to HBV. SRA could interact directly with tumor necrosis factor receptor‐associated factor 3 (TRAF3) and inhibit its K63‐linked ubiquitination. Moreover, we provided evidence that SRA negatively regulates the stability of TRAF3 protein by promoting the recruitment of OTUB1 to TRAF3. Our findings indicate that SRA plays a crucial role in innate immune signaling by targeting TRAF3 for degradation and balancing the innate antiviral immunity.

Inhibition of Antiviral Innate Immunity by Avibirnavirus VP3 via Blocking TBK1-TRAF3 Complex Formation and IRF3 Activation

“…At the early stage of virus infection, K63-linked polyubiquitination of TRAF3 contributes to the formation of the IFN antiviral signaling complex for promoting IFN induction; however, at the late stage of virus infection, K48linked polyubiquitination of TRAF3 mediated by TRIAD3A facilitates its degradation through the ubiquitin proteasome pathway (20,49). Thus, many viruses have also employed multiple strategies to regulate the ubiquitination of TRAF3 for supporting viral replication (50)(51)(52)(53). A recent report demonstrated that K33-linked polyubiquitination of TRAF3 orchestrated the expulsion of intracellular bacteria from the TLR4 pathway (29).…”

OTUB1 Promotes Progression and Proliferation of Prostate Cancer via Deubiquitinating and Stabling Cyclin E1

“…OTUB1 regulated not only cancer metastasis but also chemotherapy resistance, U Karunarathna et al had found that OTUB1 inhibited the ubiquitination and degradation of FOXM1 in breast cancer and mediated epirubicin resistance (37). Recently, some researchers had proved OTUB1 could weaken interferon response to hepatitis B virus infection (38). The effect of OTUB1 in varies tumors reminded us that OTUB1 might play important role during cancer evolution process and some physiological activities.…”

Deciphering the Fine-Tuning of the Retinoic Acid-Inducible Gene-I Pathway in Teleost Fish and Beyond

“…YOD1, which acts at a later step along the pathway to abrogate the formation of prion-like aggregates of MAVS ( 80 ), has a limited effect on IFN promotor induction at an early time point post-stimulation. In contrast, mammalian OTUB1 and USP22 were reported with opposite regulatory effects on the RLR pathway ( 67 – 69 , 103 , 104 ). The inhibitory effect observed after ectopic expression of the fish orthologs may be a result of the inherent bias associated with the overexpression of enzymatically-active protein, mislocalization and inadequate cell type and does not allow to distinguish the opposite functions previously described in mammals.…”