title: Ubiquitin-specific proteases 25 negatively regulates virus-induced type I interferon signaling.
abstract: Ubiquitination and deubiquitination have emerged as critical regulatory processes in the virus-triggered type I interferon (IFN) induction pathway. In this study, we carried out a targeted siRNA screen of 54 ubiquitin-specific proteases (USPs) and identified USP25 as a negative regulator of the virus-triggered type I IFN signaling pathway. Overexpression of USP25 inhibited virus-induced activation of IFN-β, interferon regulation factor 3 (IRF3) and nuclear factor-kappa B (NF-κB), as well as the phosphorylation of IRF3 and NF-κB subunit p65. Furthermore, Knockdown of USP25 potentiated virus-induced induction of the IFN-β. In addition, detailed analysis demonstrated that USP25 cleaved lysine 48- and lysine 63-linked polyubiquitin chains in vitro and in vivo, and its deubiquitinating enzyme (DUB) activity, were dependent on a cysteine residue (Cys178) and a histidine residue (His607). USP25 mutants lacking DUB activity lost the ability to block virus-induced type I IFN to some degree. Mechanistically, USP25 deubiquitinated retinoic acid-inducible gene I (RIG-I), tumornecrosis factor (TNF) receptor-associated factor 2 (TRAF2), and TRAF6 to inhibit RIG-I-like receptor-mediated IFN signaling. Our findings suggest that USP25 is a novel DUB negatively regulating virus-induced type I IFN production.
authors.affiliation: State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Zhong
authors.forename: Dang
authors.initials: D
authors.lastname: Wang
authors.forename: Liurong
authors.initials: L
authors.lastname: Fang
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Luo
authors.forename: Min
authors.initials: M
authors.lastname: Shang
authors.forename: Chao
authors.initials: C
authors.lastname: Ouyang
authors.forename: Haiping
authors.initials: H
authors.lastname: Ouyang
authors.forename: Huanchun
authors.initials: H
authors.lastname: Chen
authors.forename: Shaobo
authors.initials: S
authors.lastname: Xiao
mesh_terms: D005786:Gene Expression Regulation; D020868:Gene Silencing; D017930:Genes, Reporter; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D029082:Sendai virus / Q000235:genetics*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; C437968:PLAAT4 protein, human; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D051996:Transcription Factor RelA; C404488:USP25 protein, human; D016899:Interferon-beta; D008156:Luciferases; D043222:Ubiquitin Thiolesterase; D008239:Lysine