title: Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination.
abstract: Signal transduction from the T cell receptor (TCR) is crucial for T cell-mediated immune responses and, when deregulated, also contributes to the development of autoimmunity. How TCR signaling is regulated is incompletely understood. In this study, we demonstrate a ubiquitin-dependent mechanism in which the deubiquitinase Otud7b has a crucial role in facilitating TCR signaling. Upon TCR ligation, Otud7b is rapidly recruited to the tyrosine kinase Zap70, a central mediator of TCR-proximal signaling. Otud7b deficiency attenuates the activation of Zap70 and its downstream pathways and impairs T cell activation and differentiation, rendering mice refractory to T cell-mediated autoimmune and inflammatory responses. Otud7b facilitated Zap70 activation by deubiquitinating Zap70, thus preventing the association of Zap70 with the negative-regulatory phosphatases Sts1 and Sts2. These findings establish Otud7b as a positive regulator of TCR-proximal signaling and T cell activation, highlighting the importance of deubiquitination in regulating Zap70 function.
authors.affiliation: Department of Rheumatology and Immunology, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030 Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, 581 83 Linköping, Sweden.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030 Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China.
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030 Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030 College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Chang
authors.affiliation: Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zou
authors.affiliation: Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX 77030 Graduate School of Biomedical Sciences, University of Texas, Houston, TX 77030 ssun@mdanderson.org.
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D000375:Aging / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D002454:Cell Differentiation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D010450:Endopeptidases / Q000172:deficiency / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D008231:Lymphopenia / Q000276:immunology; D008239:Lysine / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D054875:Ubiquitination; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*; D000072017:Deubiquitinating Enzymes
chemical_list: D010450:Endopeptidases; D000939:Epitopes; D008239:Lysine; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; C578787:Otud7b protein, mouse; D000072017:Deubiquitinating Enzymes