title: Usp9X Is Required for Lymphocyte Activation and Homeostasis through Its Control of ZAP70 Ubiquitination and PKCβ Kinase Activity.
abstract: To achieve a durable adaptive immune response, lymphocytes must undergo clonal expansion and induce a survival program that enables the persistence of Ag-experienced cells and the development of memory. During the priming phase of this response, CD4(+)T lymphocytes either remain tolerized or undergo clonal expansion. In this article, we show that Usp9X functions as a positive regulatory switch during T lymphocyte priming through removal of inhibitory monoubiquitination from ZAP70. In the absence of Usp9X, an increased amount of ZAP70 localized to early endosomes consistent with the role of monoubiquitin in endocytic sorting. Usp9X becomes competent to deubiquitinate ZAP70 through TCR-dependent phosphorylation and enhancement of its catalytic activity and association with the LAT signalosome. In B lymphocytes, Usp9X is required for the induction of PKCβ kinase activity after BCR-dependent activation. Accordingly, inUsp9Xknockout B cells, there was a significant reduction in phospho-CARMA1 levels that resulted in reduced CARMA1/Bcl-10/MALT-1 complex formation and NF-κB-dependent cell survival. The pleiotropic effect of Usp9X during Ag-receptor signaling highlights its importance for the development of an effective and durable adaptive immune response.
authors.affiliation: Department of Physiological Chemistry, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Edwina
authors.initials: E
authors.lastname: Naik
authors.affiliation: Department of Physiological Chemistry, Genentech, Inc., South San Francisco, CA 94080 dixit@gene.com.
authors.forename: Vishva M
authors.initials: VM
authors.lastname: Dixit
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001402:B-Lymphocytes / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D020169:Caspases / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival; D010450:Endopeptidases / Q000235:genetics* / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000235:genetics; D009363:Neoplasm Proteins / Q000276:immunology; D010766:Phosphorylation; D064546:Protein Kinase C beta / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; C110810:LAT protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D064546:Protein Kinase C beta; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; C404328:Usp9x protein, mouse; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein