STUB1 regulates antiviral RNAi through inducing ubiquitination and degradation of Dicer and AGO2 in mammals  

作　　者：Shumin Zhang Xuhua Zhang Yuanyuan Bie Jing Kong An Wang Yang Qiu Xi Zhou 

机构地区：[1]State Key Laboratory of Virology,Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430071,China [2]University of Chinese Academy of Sciences,Beijing 100049,China

出　　处：《Virologica Sinica》2022年第4期569-580,共12页中国病毒学（英文版）

基　　金：the National Natural Science Foundation of China(31970169 to X.Z.and 82172269 and 81873964 to Y.Q.);the International Partnership Program of Chinese Academy of Sciences(153B42KYSB20200004 to X.Z.);the Young Top-notch Talent Cultivation Program of Hubei Province(Y.Q.);the Grant from the CAS Youth Innovation Promotion Association(2020332 to Y.Q.);the Hubei Province Natural Science Funds for Distinguished Young Scholar(2021CFA047 to Y.Q.);the Young Top-notch Talent Cultivation Program of Hubei Province(Y.Q.)。

摘　　要：RNA interference(RNAi)is an intrinsic antiviral immune mechanism conserved in diverse eukaryotic organisms.However,the mechanism by which antiviral RNAi in mammals is regulated is poorly understood.In this study,we uncovered that the E3 ubiquitin ligase STIP1 homology and U-box-containing protein 1(STUB1)was a new regulator of the RNAi machinery in mammals.We found that STUB1 interacted with and ubiquitinated AGO2,and targeted it for degradation in a chaperon-dependent manner.STUB1 promoted the formation of Lys48(K48)-linked polyubiquitin chains on AGO2,and facilitated AGO2 degradation through ubiquitin-proteasome system.In addition to AGO2,STUB1 also induced the protein degradation of AGO1,AGO3 and AGO4.Further investigation revealed that STUB1 also regulated Dicer's ubiquitination via K48-linked polyubiquitin and induced the degradation of Dicer as well as its specialized form,termed antiviral Dicer(avi Dicer)that expresses in mammalian stem cells.Moreover,we found that STUB1 deficiency up-regulated Dicer and AGO2,thereby enhancing the RNAi response and efficiently inhibiting viral replication in mammalian cells.Using the newborn mouse model of Enterovirus A71(EV-A71),we confirmed that STUB1 deficiency enhanced the virus-derived si RNAs production and antiviral RNAi,which elicited a potent antiviral effect against EV-A71 infection in vivo.In summary,our findings uncovered that the E3 ubiquitin ligase STUB1 was a general regulator of the RNAi machinery by targeting Dicer,avi Dicer and AGO1–4.Moreover,STUB1 regulated the RNAi response through mediating the abundance of Dicer and AGO2 during viral infection,thereby providing novel insights into the regulation of antiviral RNAi in mammals.

关 键 词：Antiviral RNAi STIP1 homology and U-box-containing protein 1(STUB1) Argonaute 2(AGO2) DICER 

分 类 号：S852.4[农业科学—基础兽医学]