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Nat Commun. 2018 Mar 28;9(1):1243. doi: 10.1038/s41467-018-03563-8.

MLL5 suppresses antiviral innate immune response by facilitating STUB1-mediated RIG-I degradation.

Author information

1
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
2
Institute of Biology and Medical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, 215123, China.
3
School of Life Sciences, Shanghai University, 99 Shangda Road, Shanghai, 200444, China.
4
Shanghai Institute of Immunology, Shanghai Jiaotong University, 280 South Chongqing Road, Shanghai, 200025, China.
5
Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
6
Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 8 Medical Drive, MD 7 #04-06, Singapore, 117597, Singapore.
7
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China. yan_zhang@sibs.ac.cn.

Abstract

Trithorax group protein MLL5 is an important epigenetic modifier that controls cell cycle progression, chromatin architecture maintenance, and hematopoiesis. However, whether MLL5 has a role in innate antiviral immunity is largely unknown. Here we show that MLL5 suppresses the RIG-I-mediated anti-viral immune response. Mll5-deficient mice infected with vesicular stomatitis virus show enhanced anti-viral innate immunity, reduced morbidity, and viral load. Mechanistically, a fraction of MLL5 located in the cytoplasm interacts with both RIG-I and its E3 ubiquitin ligase STUB1, which promotes K48-linked polyubiquitination and proteasomal degradation of RIG-I. MLL5 deficiency attenuates the RIG-I and STUB1 association, reducing K48-linked polyubiquitination and accumulation of RIG-I protein in cells. Upon virus infection, nuclear MLL5 protein translocates from the nucleus to the cytoplasm inducing STUB1-mediated degradation of RIG-I. Our study uncovers a previously unrecognized role for MLL5 in antiviral innate immune responses and suggests a new target for controlling viral infection.

PMID:
29593341
PMCID:
PMC5871759
DOI:
10.1038/s41467-018-03563-8
[Indexed for MEDLINE]
Free PMC Article

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