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J Immunol. 2019 Dec 1;203(11):2827-2836. doi: 10.4049/jimmunol.1801338. Epub 2019 Oct 28.

UBASH3A Regulates the Synthesis and Dynamics of TCR-CD3 Complexes.

Ge Y1,2, Paisie TK3,2,4, Chen S2,4,5,6,7, Concannon P1,2.

Author information

1
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610; yange09@ufl.edu patcon@ufl.edu.
2
Genetics Institute, University of Florida, Gainesville, FL 32610.
3
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610.
4
Genetics and Genomics Graduate Program, University of Florida, Gainesville, FL 32610.
5
Department of Biology, University of Florida, Gainesville, FL 32611.
6
Plant Molecular and Cellular Biology Program, University of Florida, Gainesville, FL 32611; and.
7
Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL 32610.

Abstract

The TCR-CD3 complex is a multicomponent membrane receptor, the expression of which is tightly regulated in thymocytes, as well as in mature T cells both at steady state and upon stimulation. In this study, we report novel roles for UBASH3A in TCR-CD3 synthesis and turnover. UBASH3A is a negative regulator of T cell function and plays a broad role in autoimmunity. We show that modulation of UBASH3A levels in unstimulated Jurkat cells leads to altered amounts of total cellular CD3 chains and of cell-surface TCR-CD3 complexes; in contrast, UBASH3A does not affect the level of cell-surface CD28, an important T cell costimulatory receptor. Upon TCR engagement, UBASH3A enhances the downmodulation of cell-surface TCR-CD3. Mass spectrometry and protein-protein interaction studies uncover novel associations between UBASH3A and components of several cellular pathways involved in the regulation of TCR-CD3 turnover and dynamics, including endoplasmic reticulum-associated protein degradation, cell motility, endocytosis, and endocytic recycling of membrane receptors. Finally, we demonstrate that the SH3 domain of UBASH3A mediates its binding to CBL-B, an E3 ubiquitin ligase that negatively regulates CD28-mediated signaling and, hence, T cell activation. In summary, this study provides new mechanistic insights into how UBASH3A regulates T cell activation and contributes to autoimmunity. The interaction between UBASH3A and CBL-B may synergistically inhibit T cell function and affect risk for type 1 diabetes, as both genes have been shown to be associated with this autoimmune disease.

PMID:
31659016
PMCID:
PMC6938261
[Available on 2020-12-01]
DOI:
10.4049/jimmunol.1801338

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