MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner

PLoS Pathogens

Jianzhong Xi¹  Chenguang Wang¹  Run Fang¹  Zhengfan Jiang²  Jianli Tao²  Xiang Zhou²  Ji-Ming Feng³  Qifei Jiang³  Yukun Guan³ 

[1] Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China;Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Peking University, Beijing, China;State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China

关键词: 293T cells;    Phosphorylation;    Immunoprecipitation;    Transcription factors;    Ligases;    Precipitates;    Enzyme-linked immunoassays;    HeLa cells;   

DOI  :  10.1371/journal.ppat.1006720

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Mitochondrial antiviral-signaling protein (MAVS) transmits signals from RIG-I-like receptors after RNA virus infections. However, the mechanism by which MAVS activates downstream components, such as TBK1 and IKKα/β, is unclear, although previous work suggests the involvement of NEMO or TBK1-binding proteins TANK, NAP1, and SINTBAD. Here, we report that MAVS-mediated innate immune activation is dependent on TRAFs, partially on NEMO, but not on TBK1-binding proteins. MAVS recruited TBK1/IKKε by TRAFs that were pre-associated with TBK1/IKKε via direct interaction between the coiled-coil domain of TRAFs and the SDD domain of TBK1/IKKε. TRAF2−/−3−/−5−/−6−/− cells completely lost RNA virus responses. TRAFs’ E3 ligase activity was required for NEMO activation by synthesizing ubiquitin chains that bound to NEMO for NF-κB and TBK1/IKKε activation. NEMO-activated IKKα/β were important for TBK1/IKKε activation through IKKα/β-mediated TBK1/IKKε phosphorylation. Moreover, individual TRAFs differently mediated TBK1/IKKε activation and thus fine-tuned antiviral immunity under physiological conditions.

【 授权许可】

CC BY