title: Deubiquitinase USP2a Sustains Interferons Antiviral Activity by Restricting Ubiquitination of Activated STAT1 in the Nucleus.
abstract: STAT1 is a critical transcription factor for regulating host antiviral defenses. STAT1 activation is largely dependent on phosphorylation at tyrosine 701 site of STAT1 (pY701-STAT1). Understanding how pY701-STAT1 is regulated by intracellular signaling remains a major challenge. Here we find that pY701-STAT1 is the major form of ubiquitinated-STAT1 induced by interferons (IFNs). While total STAT1 remains relatively stable during the early stages of IFNs signaling, pY701-STAT1 can be rapidly downregulated by the ubiquitin-proteasome system. Moreover, ubiquitinated pY701-STAT1 is located predominantly in the nucleus, and inhibiting nuclear import of pY701-STAT1 significantly blocks ubiquitination and downregulation of pY701-STAT1. Furthermore, we reveal that the deubiquitinase USP2a translocates into the nucleus and binds to pY701-STAT1, and inhibits K48-linked ubiquitination and degradation of pY701-STAT1. Importantly, USP2a sustains IFNs-induced pY701-STAT1 levels, and enhances all three classes of IFNs- mediated signaling and antiviral activity. To our knowledge, this is the first identified deubiquitinase that targets activated pY701-STAT1. These findings uncover a positive mechanism by which IFNs execute efficient antiviral signaling and function, and may provide potential targets for improving IFNs-based antiviral therapy.
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Yukang
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Yibo
authors.initials: Y
authors.lastname: Zuo
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Qian
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Chang
authors.identifier: 0000-0002-5246-4654
authors.initials: C
authors.lastname: Liu
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Guo
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Liting
authors.identifier: 0000-0002-6797-6433
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Xiaofang
authors.identifier: 0000-0003-2239-7080
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Qian
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Lemin
authors.initials: L
authors.lastname: Li
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ge
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Dai
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Jiangsu, China.
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Infection and Immunity, Soochow University, Jiangsu, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D010450:Endopeptidases / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007372:Interferons / Q000276:immunology*; D008856:Microscopy, Fluorescence; D021381:Protein Transport / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D029082:Sendai virus / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination; D018116:Vesiculovirus / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology*
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007372:Interferons; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase