USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA

Liya Ye; Qiang Zhang; Tianzi Liuyu; Zhigao Xu; Meng-Xin Zhang; Min-Hua Luo; Wen-Bo Zeng; Qiyun Zhu; Dandan Lin; Bo Zhong

doi:10.1371/journal.ppat.1007680

USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA

PLoS Pathog. 2019 Apr 3;15(4):e1007680. doi: 10.1371/journal.ppat.1007680. eCollection 2019 Apr.

Authors

Liya Ye^{1

2}, Qiang Zhang^{1

2}, Tianzi Liuyu^{1

2}, Zhigao Xu³, Meng-Xin Zhang^{1

2}, Min-Hua Luo⁴, Wen-Bo Zeng⁴, Qiyun Zhu⁵, Dandan Lin⁶, Bo Zhong^{1

2}

Affiliations

¹ Department of Gastrointestinal Surgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, China.
² College of Life Sciences, Wuhan University, Wuhan, China.
³ Department of Pathology, Center for Pathology and Molecular Diagnostics, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁴ State Key Laboratory of Virology, CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
⁵ State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
⁶ Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.

Abstract

Mediator of IRF3 activation (MITA, also known as STING and ERIS) is an essential adaptor protein for cytoplasmic DNA-triggered signaling and involved in innate immune responses, autoimmunity and tumorigenesis. The activity of MITA is critically regulated by ubiquitination and deubiquitination. Here, we report that USP49 interacts with and deubiquitinates MITA after HSV-1 infection, thereby turning down cellular antiviral responses. Knockdown or knockout of USP49 potentiated HSV-1-, cytoplasmic DNA- or cGAMP-induced production of type I interferons (IFNs) and proinflammatory cytokines and impairs HSV-1 replication. Consistently, Usp49-/- mice exhibit resistance to lethal HSV-1 infection and attenuated HSV-1 replication compared to Usp49+/+ mice. Mechanistically, USP49 removes K63-linked ubiquitin chains from MITA after HSV-1 infection which inhibits the aggregation of MITA and the subsequent recruitment of TBK1 to the signaling complex. These findings suggest a critical role of USP49 in terminating innate antiviral responses and provide insights into the complex regulatory mechanisms of MITA activation.

Publication types

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

MeSH terms

Animals
Antiviral Agents
HEK293 Cells
Herpes Simplex / immunology
Herpes Simplex / prevention & control*
Herpes Simplex / virology
Herpesvirus 1, Human
Humans
Immunity, Innate / immunology*
Lysine / chemistry
Lysine / metabolism*
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Signal Transduction
THP-1 Cells
Ubiquitin Thiolesterase / genetics
Ubiquitin Thiolesterase / metabolism*
Ubiquitination
Virus Replication

Substances

Antiviral Agents
Membrane Proteins
STING1 protein, human
USP49 protein, human
Ubiquitin Thiolesterase
Lysine

Grants and funding

This study was supported by grants from National Key Research and Development Program of China (2018YFC1004601), Natural Science Foundation of China (31601131, 31671454, and 31622036), Natural Science Foundation of Hubei Province (2018CFA016), Health Commission of Hubei Province (WJ2018H0028), Wuhan University (2042017kf0199 and 2042017kf0242), and State Key Laboratory of Veterinary Etiological Biology (SKLVEB2017KFKT004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.