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

Authors

Run Fang, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Qifei Jiang, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Xiang Zhou, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Chenguang Wang, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Yukun Guan, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Jianli Tao, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.
Jianzhong Xi, Institute of Molecular Medicine, Peking University, Beijing, China.
Ji-Ming Feng, Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States of America.
Zhengfan Jiang, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.

Document Type

Article

Publication Date

11-1-2017

Abstract

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.

Publication Source (Journal or Book title)

PLoS pathogens

First Page

e1006720

Recommended Citation

Fang, R., Jiang, Q., Zhou, X., Wang, C., Guan, Y., Tao, J., Xi, J., Feng, J., & Jiang, Z. (2017). MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner. PLoS pathogens, 13 (11), e1006720. https://doi.org/10.1371/journal.ppat.1006720