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

Peipei Zhou, Xiaodan Ding, Xiaoling Wan, Lulu Liu, Xiujie Yuan, Wei Zhang, Xinhui Hui, Guangxun Meng, Hui Xiao, Bin Li, Jin Zhong, Fajian Hou, Lihwen Deng and Yan Zhang ()
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Peipei Zhou: University of Chinese Academy of Sciences
Xiaodan Ding: University of Chinese Academy of Sciences
Xiaoling Wan: University of Chinese Academy of Sciences
Lulu Liu: University of Chinese Academy of Sciences
Xiujie Yuan: University of Chinese Academy of Sciences
Wei Zhang: University of Chinese Academy of Sciences
Xinhui Hui: University of Chinese Academy of Sciences
Guangxun Meng: University of Chinese Academy of Sciences
Hui Xiao: University of Chinese Academy of Sciences
Bin Li: Shanghai Jiaotong University
Jin Zhong: University of Chinese Academy of Sciences
Fajian Hou: Chinese Academy of Sciences
Lihwen Deng: National University of Singapore
Yan Zhang: University of Chinese Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03563-8

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