title: Ubiquitin-specific protease 2b negatively regulates IFN-β production and antiviral activity by targeting TANK-binding kinase 1.
abstract: TANK-binding kinase 1 (TBK1) is essential for IFN regulatory factor 3 activation and IFN-β production downstream of various innate receptors. However, how TBK1 activation is terminated is not well defined. In this study, we identified ubiquitin-specific protease (USP) 2b as a new negative regulator for TBK1 activation. Overexpression of USP2b inhibited retinoic acid-inducible gene-I-mediated IFN-β signaling; in contrast, knockdown of USP2b expression by small interfering RNA enhanced retinoic acid-inducible gene-I-mediated IFN-β signaling. Coimmunoprecipitation experiments demonstrated that USP2b interacted with TBK1. As a deubiquitinating enzyme, USP2b was demonstrated to cleave K63-linked polyubiquitin chains from TBK1 to inhibit TBK1 kinase activity. Consistent with the inhibitory roles of USP2b on TBK1 activation, knockdown of USP2b significantly inhibited the replication of vesicular stomatitis virus, whereas overexpression of USP2b resulted in enhanced replication of vesicular stomatitis virus. Therefore, our findings demonstrated that USP2b deubiquitinates K63-linked polyubiquitin chains from TBK1 to terminate TBK1 activation and negatively regulate IFN-β signaling and antiviral immune response.
authors: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China; andKey Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors: Lei
authors: L
authors: Zhang
authors: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China; andKey Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors: Xueying
authors: X
authors: Zhao
authors: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China; andKey Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors: Meng
authors: M
authors: Zhang
authors: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China; andKey Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors: Wei
authors: W
authors: Zhao
authors: Department of Immunology, Shandong University School of Medicine, Jinan, Shandong 250012, China; andKey Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Medicine, Jinan, Shandong 250012, China cgao@sdu.edu.cn.
authors: Chengjiang
authors: C
authors: Gao
mesh_terms: D010450:Endopeptidases / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology*; D025821:Polyubiquitin / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination / Q000235:genetics / Q000276:immunology; D018116:Vesiculovirus / Q000502:physiology*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
chemical_list: D025821:Polyubiquitin; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase