USP22 promotes IRF3 nuclear translocation and antiviral responses by deubiquitinating the importin protein KPNA2

被引：59

作者：

Cai, Zeng ^{[1
,2
]}

Zhang, Meng-Xin ^{[1
,2
]}

Tang, Zhen ^{[1
,2
]}

Zhang, Qiang ^{[1
,2
]}

Ye, Jing ^{[1
,2
]}

Xiong, Tian-Chen ^{[1
,2
]}

Zhang, Zhi-Dong ^{[1
,2
]}

Zhong, Bo ^{[1
,2
]}

机构：

[1] Wuhan Univ, Coll Life Sci, Dept Virol, Dept Gastrointestinal Surg,Zhongnan Hosp, Wuhan, Peoples R China

[2] Wuhan Univ, Frontier Sci Ctr Immunol & Metab, Med Res Inst, Dept Immunol, Wuhan, Peoples R China

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2020年 / 217卷 / 05期

基金：

中国国家自然科学基金;

关键词：

NF-KAPPA-B; CYCLIC GMP-AMP; ADAPTER PROTEIN; LOCALIZATION SIGNAL; INNATE; TRANSPORT; PHOSPHORYLATION; IDENTIFICATION; PROLIFERATION; MECHANISMS;

D O I：

10.1084/jem.20191174

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

USP22 is a cytoplasmic and nuclear deubiquitinating enzyme, and the functions of cytoplasmic USP22 are unclear. Here, we discovered that cytoplasmic USP22 promoted nuclear translocation of IRF3 by deubiquitianting and stabilizing KPNA2 after viral infection. Viral infection induced USP22-IRF3 association in the cytoplasm in a KPNA2-depedent manner, and knockdown or knockout of USP22 or KPNA2 impaired IRF3 nuclear translocation and expression of downstream genes after viral infection. Consistently, Cre-ER Usp22(fl/fl) or Lyz2-Cre Usp22(fl/fl) mice produced decreased levels of type I IFNs after viral infection and exhibited increased susceptibility to lethal viral infection compared with the respective control littermates. Mechanistically, USP22 deubiquitinated and stabilized KPNA2 after viral infection to facilitate efficient nuclear translocation of IRF3. Reconstitution of KPNA2 into USP22 knockout cells restored virus-triggered nuclear translocation of IRF3 and cellular antiviral responses. These findings define a previously unknown function of cytoplasmic USP22 and establish a mechanistic link between USP22 and IRF3 nuclear translocation that expands potential therapeutic strategies for infectious diseases.

引用

页数：25

共 54 条

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