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A non‐canonical role of the p97 complex in RIG ‐I antiviral signaling
Author(s) -
Hao Qian,
Jiao Shi,
Shi Zhubing,
Li Chuanchuan,
Meng Xia,
Zhang Zhen,
Wang Yanyan,
Song Xiaomin,
Wang Wenjia,
Zhang Rongguang,
Zhao Yun,
Wong Catherine CL,
Zhou Zhaocai
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201591888
Subject(s) - biology , rig i , ubiquitin , innate immune system , microbiology and biotechnology , vesicular stomatitis virus , ubiquitin ligase , antiviral protein , viral replication , rna , biochemistry , virus , virology , receptor , gene
RIG ‐I is a well‐studied sensor of viral RNA that plays a key role in innate immunity. p97 regulates a variety of cellular events such as protein quality control, membrane reassembly, DNA repair, and the cell cycle. Here, we report a new role for p97 with Npl4‐Ufd1 as its cofactor in reducing antiviral innate immune responses by facilitating proteasomal degradation of RIG ‐I. The p97 complex is able to directly bind both non‐ubiquitinated RIG ‐I and the E3 ligase RNF 125, promoting K48‐linked ubiquitination of RIG ‐I at residue K181. Viral infection significantly strengthens the interaction between RIG ‐I and the p97 complex by a conformational change of RIG ‐I that exposes the CARD s and through K63‐linked ubiquitination of these CARD s. Disruption of the p97 complex enhances RIG ‐I antiviral signaling. Consistently, administration of compounds targeting p97 ATP ase activity was shown to inhibit viral replication and protect mice from vesicular stomatitis virus ( VSV ) infection. Overall, our study uncovered a previously unrecognized role for the p97 complex in protein ubiquitination and revealed the p97 complex as a potential drug target in antiviral therapy.