BRCC36 functions noncatalytically to promote antiviral response by maintaining STAT1 protein stability

Abstract

Viral infection is a serious threat to both normal population and clinical patients. STAT1 plays central roles in host defense against viral infection. How STAT1 protein maintains stable in different conditions remains largely unknown. Here, we identified BRCC36 as a potent regulator of STAT1 protein stability. Mechanistically, BRCC36 maintains STAT1 levels by utilizing USP13 to form a balanced complex for antagonizing Smurf1‐mediated degradation. Importantly, cellular BRCC36 deficiency results in rapid downregulation of STAT1 during viral infection, whereas a supplement of BRCC36 maintains STAT1 protein levels and host antiviral immunity in vivo. Moreover, we revealed that BRCC36 expression was downregulated in allogeneic HSC transplantation (allo‐HSCT) mice that showed increased susceptibility to viral infection. Supplementing BRCC36 enhanced antiviral response of allo‐HSCT mice by maintaining STAT1 stability. This study uncovers a critical role of BRCC36 in STAT1 protein stability and could provide potential strategies for enhancing clinical antiviral therapy.

The role of SMURFs in non‐cancerous diseases

“…Secondly, BRCC36, a Zn 2+ -dependent deubiquitinase, binds to STAT1 and restricts SMURF1-induced STAT1 ubiquitination by simultaneously recruiting the deubiquitinase ubiquitin-specific protease 13 (USP13) to the complex. 177 Furthermore, the maintenance of SMURF1 turnover and stability by ubiquitin-specific protease 5 (USP5) was achieved through the reduction of Lys-63-linked ubiquitination level of SMURF1, resulting in the inhibition of IFN-induced antiviral activity by decreasing STAT1 levels. 178 The precise mechanism underlying the regulation of SMURF1 polyubiquitination to balance IFN antiviral signaling requires further investigation.…”

An Integrated View of Deubiquitinating Enzymes Involved in Type I Interferon Signaling, Host Defense and Antiviral Activities

“…The ubiquitination and deubiquitination regulation events of STAT1 and its associated effects on the innate immune response have been increasingly investigated in recent years. For example, the three deubiquitinating enzymes BRCC36, USP13, and USP39 interact with STAT1 and decrease the K63-, K48- and K6-linked polyubiquitin chains of STAT1 respectively ( 110 , 115 , 118 ). These three DUBs positively regulate IFN-mediated antiviral activities and have been proposed to antagonize the degradation rate of STAT1 mediated by two E3 ligases, SLIM ( 133 ) and SMURF1 ( 134 ).…”

“…These three DUBs positively regulate IFN-mediated antiviral activities and have been proposed to antagonize the degradation rate of STAT1 mediated by two E3 ligases, SLIM ( 133 ) and SMURF1 ( 134 ). More specifically, BRCC36 deficiency leads to a rapid downregulation of STAT1 during viral infection, whereas complementation by BRCC36 can rescue the STAT1 expression levels and suppress virus infection ( 110 ). BRCC36 sustains STAT1 protein turnover by recruiting USP13 to form a balanced complex to antagonize the SMURF1-mediated degradation of STAT1 ( 110 ).…”

“…More specifically, BRCC36 deficiency leads to a rapid downregulation of STAT1 during viral infection, whereas complementation by BRCC36 can rescue the STAT1 expression levels and suppress virus infection ( 110 ). BRCC36 sustains STAT1 protein turnover by recruiting USP13 to form a balanced complex to antagonize the SMURF1-mediated degradation of STAT1 ( 110 ). More specifically, USP13 positively regulates the antiviral activity of IFNα against DEN-2 virus replication by deubiquitinating and stabilizing STAT1 ( 115 ).…”

“…In the case of IFNAR-mediated downstream signaling, some other DUBs also implement their functions beyond their protease activities. For example, BRCC36 functions noncatalytically by recruiting USP13 to counteract the SMURF1-mediated degradation of STAT1, and this effect enhances the stability of STAT1 and improves host antiviral efficiency ( 110 ). Additionally, USP12 positively regulates IFN antiviral signaling independently of its deubiquitinase activity.…”