title: Regulation of T cell function by the ubiquitin-specific protease USP9X via modulating the Carma1-Bcl10-Malt1 complex.
abstract: The ubiquitin conjugation system plays an important role in immune regulation; however, the ubiquitin-specific proteases (USPs) that carry out deubiquitination of cellular substrates are poorly understood. Here we show that in vivo knockdown of the deubiquitinating enzyme USP9X attenuates T-cell proliferation. In addition, naïve CD4(+) T cells from USP9X knockdown chimeric mice display decreased cytokine production and T helper cell differentiation in vitro, which we confirmed in vivo by performing adoptive transfer of transgenic T cells and subsequent immunization. USP9X silencing in both a human T-cell line and mouse primary T cells reduced T-cell receptor (TCR) signaling-induced NF-κB activation. Mechanistically, USP9X interacts with Bcl10 of the Carma1-Bcl10-Malt1 (CBM) complex and removes the TCR-induced ubiquitin chain from Bcl10, which facilitates the association of Carma1 with Bcl0-Malt1. These results demonstrate that USP9X is a crucial positive regulator of the TCR signaling pathway and is required for T-cell function through the modulation of CBM complex formation.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Park
authors.forename: Hyung-seung
authors.initials: HS
authors.lastname: Jin
authors.forename: Yun-Cai
authors.initials: YC
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D020169:Caspases / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D046912:Multiprotein Complexes / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D043222:Ubiquitin Thiolesterase
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; D016207:Cytokines; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; C404328:Usp9x protein, mouse; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
keywords: posttranslational modification; signal transduction