Ubiquitin-Conjugating Enzyme 2S Enhances Viral Replication by Inhibiting Type I IFN Production through Recruiting USP15 to Deubiquitinate TBK1

Li Huang; Hongyang Liu; Kunli Zhang; Qingwen Meng; Liang Hu; Yuanfeng Zhang; Zhida Xiang; Jiangnan Li; Yuying Yang; Yali Chen; Shangjin Cui; Hong Tang; Huadong Pei; Zhigao Bu; Changjiang Weng

doi:10.1016/j.celrep.2020.108044

Ubiquitin-Conjugating Enzyme 2S Enhances Viral Replication by Inhibiting Type I IFN Production through Recruiting USP15 to Deubiquitinate TBK1

Cell Rep. 2020 Aug 18;32(7):108044. doi: 10.1016/j.celrep.2020.108044.

Authors

Li Huang¹, Hongyang Liu², Kunli Zhang¹, Qingwen Meng¹, Liang Hu¹, Yuanfeng Zhang¹, Zhida Xiang², Jiangnan Li¹, Yuying Yang³, Yali Chen⁴, Shangjin Cui⁵, Hong Tang⁶, Huadong Pei⁷, Zhigao Bu¹, Changjiang Weng⁸

Affiliations

¹ State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China.
² State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China; College of Animal Science and Technology, Yangtze University, Jingzhou 434100, China.
³ College of Animal Science and Technology, Yangtze University, Jingzhou 434100, China.
⁴ State Key Laboratory of Proteomics, Beijing Institute of Lifeomics, Beijing 102206, China.
⁵ Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
⁶ Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
⁷ Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Science, 2300 Eye Street, N.W., Washington, DC 20037, USA; GW Cancer Center, George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA.
⁸ State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150069, China; College of Animal Science and Technology, Yangtze University, Jingzhou 434100, China. Electronic address: wengchangjiang@caas.cn.

PMID: 32814047
DOI: 10.1016/j.celrep.2020.108044

Abstract

Type I interferon (IFN) plays an essential role in the host innate immune responses. Several ubiquitin-conjugating enzyme (E2) family members were reported to regulate type I IFN production and host antiviral immune responses. However, the molecular mechanisms are still not fully understood. Here, we report that UBE2S acts as a negative regulator in the type I IFN signaling pathway. Ectopic expression of UBE2S inhibits host antiviral immune responses and enhances viral replications, whereas deficiency of UBE2S enhances host antiviral immune responses and suppresses viral replications both in vitro and in vivo. Inhibition of type І IFN production by UBE2S is independent on its E2 and E3 enzymic activity. Mechanistically, UBE2S interacts with TBK1 and recruits ubiquitin-specific protease 15 (USP15) to remove Lys63 (K63)-linked polyubiquitin chains of TBK1. Our findings reveal a role of the UBE2S-USP15-TBK1 axis in the regulation of host antiviral innate immune responses.

Keywords: IFN; TBK1; UBE2S; USP15; deubiquitination; knockout; transgenic mouse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cattle
HEK293 Cells
Humans
Interferon Type I / antagonists & inhibitors*
Interferon Type I / biosynthesis
Interferon Type I / immunology
Mice
Mice, Knockout
Mice, Transgenic
Protein Serine-Threonine Kinases / immunology*
Ubiquitin-Conjugating Enzymes / immunology*
Ubiquitination
Virus Replication / immunology*

Substances

Interferon Type I
Ube2S protein, human
Ube2s protein, mouse
Ubiquitin-Conjugating Enzymes
Tbk1 protein, mouse
Protein Serine-Threonine Kinases
TBK1 protein, human