title: Ubiquitin-specific Protease 15 Negatively Regulates Virus-induced Type I Interferon Signaling via Catalytically-dependent and -independent Mechanisms.
abstract: Viral infection triggers a series of signaling cascades, which converge to activate the transcription factors nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3), thereby inducing the transcription of type I interferons (IFNs). Although not fully characterized, these innate antiviral responses are fine-tuned by dynamic ubiquitination and deubiquitination processes. In this study, we report ubiquitin-specific protease (USP) 15 is involved in regulation of the retinoic acid-inducible gene I (RIG-I)-dependent type I IFN induction pathway. Knockdown of endogenous USP15 augmented cellular antiviral responses. Overexpression of USP15 inhibited the transcription of IFN-β. Further analyses identified histidine 862 as a critical residue for USP15's catalytic activity. Interestingly, USP15 specifically removed lysine 63-linked polyubiquitin chains from RIG-I among the essential components in RIG-I-like receptor-dependent pathway. In addition, we demonstrated that in contrast to USP15 de-ubiquitinating (DUB) activity, USP15-mediated inhibition of IFN signaling was not abolished by mutations eliminating the catalytic activity, indicating that a fraction of USP15-mediated IFN antagonism was independent of the DUB activity. Catalytically inactive USP15 mutants, as did the wild-type protein, disrupted virus-induced interaction of RIG-I and IFN-β promoter stimulator 1. Taken together, our data demonstrate that USP15 acts as a negative regulator of RIG-I signaling via DUB-dependent and independent mechanisms.
authors.affiliation: 1] State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China [2] The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1] State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China [2] The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
authors.forename: Dang
authors.initials: D
authors.lastname: Wang
authors.affiliation: 1] State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China [2] The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Zhong
authors.affiliation: 1] State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China [2] The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Luo
authors.affiliation: 1] State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China [2] The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
authors.forename: Min
authors.initials: M
authors.lastname: Shang
authors.affiliation: 1] State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China [2] The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
authors.forename: Dezhi
authors.initials: D
authors.lastname: Liu
authors.affiliation: 1] State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China [2] The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
authors.forename: Huanchun
authors.initials: H
authors.lastname: Chen
authors.affiliation: 1] State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China [2] The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
authors.forename: Liurong
authors.initials: L
authors.lastname: Fang
authors.affiliation: 1] State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China [2] The Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Xiao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D002384:Catalysis; D020134:Catalytic Domain / Q000235:genetics; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011971:Receptors, Immunologic; D015398:Signal Transduction; D064570:Ubiquitin-Specific Proteases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D018406:Virus Physiological Phenomena
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; C505371:MAVS protein, human; D011971:Receptors, Immunologic; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases