title: p38 inhibition provides anti-DNA virus immunity by regulation of USP21 phosphorylation and STING activation.
abstract: Stimulator of IFN genes (STING) is a central adaptor protein that mediates the innate immune responses to DNA virus infection. Although ubiquitination is essential for STING function, how the ubiquitination/deubiquitination system is regulated by virus infection to control STING activity remains unknown. In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus-induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING. HSV-1 infection recruited USP21 to STING at late stage by p38-mediated phosphorylation of USP21 at Ser538. Inhibition of p38 MAPK enhanced the production of IFNs in response to virus infection and protected mice from lethal HSV-1 infection. Thus, our study reveals a critical role of p38-mediated USP21 phosphorylation in regulating STING-mediated antiviral functions and identifies p38-USP21 axis as an important pathway that DNA virus adopts to avoid innate immunity responses.
authors.affiliation: Department of Central Laboratory, School of Life Science and Technology, Shanghai Tenth People's Hospital of Tongji University, Tongji University, Shanghai 200072, China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Lufan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Jin
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luan
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Hongshang
authors.initials: H
authors.lastname: Chu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Xinbo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Liao
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Central Laboratory, School of Life Science and Technology, Shanghai Tenth People's Hospital of Tongji University, Tongji University, Shanghai 200072, China.
authors.forename: Hongqi
authors.initials: H
authors.lastname: Teng
authors.affiliation: Department of Central Laboratory, School of Life Science and Technology, Shanghai Tenth People's Hospital of Tongji University, Tongji University, Shanghai 200072, China.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Central Laboratory, School of Life Science and Technology, Shanghai Tenth People's Hospital of Tongji University, Tongji University, Shanghai 200072, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Fang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China.
authors.forename: Lujian
authors.initials: L
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100000, China.|Peking University-Tsinghua University Joint Center for Life Sciences, Beijing 100084, China.
authors.forename: Zhengfan
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Tongji University, Shanghai 200072, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ge
authors.affiliation: Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Central Laboratory, School of Life Science and Technology, Shanghai Tenth People's Hospital of Tongji University, Tongji University, Shanghai 200072, China wangp@tongji.edu.cn.
authors.forename: Ping
authors.identifier: 0000-0003-0172-832X
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D004267:DNA Viruses / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000502:physiology; D007370:Interferon Type I / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D014709:Vero Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*; D000099197:STING Protein
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D043222:Ubiquitin Thiolesterase; D048051:p38 Mitogen-Activated Protein Kinases; C494232:IRF3 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C408875:USP21 protein, human