Recruitment of Phosphatase PP2A by RACK1 Adaptor Protein Deactivates Transcription Factor IRF3 and Limits Type I Interferon Signaling

被引：104

作者：

Long, Lingyun ^{[1
,2
]}

Deng, Yuezhen ^{[1
,2
]}

Yao, Fan ^{[1
,2
]}

Guan, Dongxian ^{[1
,2
]}

Feng, Yuanyuan ^{[1
,2
]}

Jiang, Hao ^{[1
,2
]}

Li, Xiaobin ^{[1
,2
]}

Hu, Pingting ^{[1
,2
]}

Lu, Xincheng ^{[1
,2
]}

Wang, Hui ^{[1
,2
]}

Li, Jingjing ^{[1
,2
]}

Gao, Xiang ^{[3
]}

Xie, Dong ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Nutr & Metab, Shanghai 200031, Peoples R China

[2] Chinese Acad Sci, Grad Sch, Shanghai 200031, Peoples R China

[3] Nanjing Univ, Model Anim Res Ctr, Key Lab Model Anim Dis Study, Minist Educ, Nanjing 210061, Jiangsu, Peoples R China

来源：

IMMUNITY | 2014年 / 40卷 / 04期

基金：

中国国家自然科学基金;

关键词：

DOUBLE-STRANDED-RNA; NF-KAPPA-B; REGULATORY FACTOR-3; NEGATIVE REGULATION; ANTIVIRAL RESPONSE; GENE-EXPRESSION; ENDOTOXIN-SHOCK; VIRUS-INFECTION; ACTIVATION; PATHWAY;

D O I：

10.1016/j.immuni.2014.01.015

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The transcription factor IRF3 is a central regulator of type I interferon (IFN) signaling. The mechanisms underlying deactivation of IRF3 are poorly understood although many studies suggest that IRF3 activity is terminated through degradation after viral infection. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I: C) stimulation or Sendai virus (SeV) infection. After challenge with LPS, poly(I: C), or low-titer SeV, activated IRF3 was dephosphorylated and returned to resting state without being degraded, although high-titer SeV infection triggered the degradation of IRF3. Furthermore, PP2A-deficient macrophages showed enhanced type I IFN signaling upon LPS, poly(I: C), and SeV challenge and protected mice from lethal vesicular stomatitis virus infection. Therefore, dephosphorylation of IRF3 is a deactivation mechanism that contributes to termination of IRF3-type I IFN signaling.

引用

页码：515 / 529

页数：15

共 36 条

[1] Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 [J].