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UBASH3A Regulates the Synthesis and Dynamics of TCR–CD3 Complexes

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UBASH3A Regulates the Synthesis and Dynamics of TCR–CD3 Complexes UBASH3A Regulates the Synthesis and Dynamics of TCR−CD3 Complexes Yan Ge, Taylor K. Paisie, Sixue Chen and Patrick Concannon This information is current as of September 28, 2021. J Immunol published online 28 October 2019 http://www.jimmunol.org/content/early/2019/10/25/jimmun ol.1801338 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/10/25/jimmunol.180133 Material 8.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 28, 2019, doi:10.4049/jimmunol.1801338 The Journal of Immunology UBASH3A Regulates the Synthesis and Dynamics of TCR–CD3 Complexes Yan Ge,*,† Taylor K. Paisie,*,†,‡ Sixue Chen,†,‡,x,{,‖ and Patrick Concannon*,† The TCR–CD3 complex is a multicomponent membrane receptor, the expression of which is tightly regulated in thymo- cytes, 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 down- modulation of cell-surface TCR–CD3. Mass spectrometry and protein–protein interaction studies uncover novel associa- tions between UBASH3A and components of several cellular pathways involved in the regulation of TCR–CD3 turnover Downloaded from 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. The Journal of http://www.jimmunol.org/ Immunology, 2019, 203: 000–000. biquitin-associated (UBA) and Src homology 3 (SH3) UBASH3A is expressed primarily in T cells and encodes a domain containing A (UBASH3A; also known as STS-2, protein called ubiquitin-associated and SH3 domain containing U TULA, and CLIP4) is a negative regulator of T cell ac- A(1,3,5).Inmice,Ubash3a mRNA is also detected in the thymus, tivation and function (1–6). Genetic variants in UBASH3A have been suggesting a role in T cell development (1). The T cell–specific associated with at least five distinct autoimmune diseases (7–18), expression pattern of UBASH3A distinguishes it from its ubiqui- suggesting a broad role of UBASH3A in autoimmunity. tously expressed paralogue, UBASH3B (also known as STS-1 and TULA-2). Unlike UBASH3A, UBASH3B has not been associated by guest on September 28, 2021 with any autoimmune disease in genome-wide association studies. *Department of Pathology, Immunology and Laboratory Medicine, University of UBASH3A has three structural domains: the N-terminal UBA, Florida, Gainesville, FL 32610; †Genetics Institute, University of Florida, Gainesville, SH3, and the C-terminal histidine phosphatase (also referred to as FL 32610; ‡Genetics and Genomics Graduate Program, University of Florida, Gainesville, FL 32610; xDepartment of Biology, University of Florida, Gainesville, FL 32611; phosphoglycerate mutase-like [PGM]) domains. The UBA do- {Plant Molecular and Cellular Biology Program, University of Florida, Gainesville, main can bind to monoubiquitin as well as lysine 63– and me- ‖ FL 32611; and Interdisciplinary Center for Biotechnology Research, University of thionine 1–linked polyubiquitin chains (5, 19). UBASH3A has Florida, Gainesville, FL 32610 four identified ubiquitination sites at lysine residues 15, 202, 309, ORCIDs: 0000-0003-2129-9438 (Y.G.); 0000-0002-6024-2744 (T.K.P.). and 358. Monoubiquitination at Lys202 causes UBASH3A to adopt Received for publication October 4, 2018. Accepted for publication September 27, a closed conformation, which prevents the binding of the UBA 2019. domain to substrates in trans (19). The SH3 domain interacts with This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK106718, DK046635, and DK085678 (to P.C.) and by Advanced dynamin (20), which is required for endocytosis, and with CBL Postdoctoral Fellowship Award 3-APF-2016-177-A-N from the Juvenile Diabetes (21, 22), an E3 ubiquitin ligase. The PGM domain mediates self- Research Foundation (to Y.G.). dimerization (23). Despite structural similarity, the PGM domain Y.G. and P.C. conceived the study, interpreted the data, and wrote the manuscript. of UBASH3A exhibits only very weak, possibly acid-dependent, Y.G. and T.K.P. performed the experiments. Y.G. analyzed the data. S.C. assisted in the design and analysis of the mass spectrometry experiments. phosphatase activity (2, 24) compared with UBASH3B, which has Address correspondence and reprint requests to Dr. Yan Ge or Dr. Patrick Concannon, readily demonstrable phosphatase activity in vitro and suppresses Department of Pathology, Immunology and Laboratory Medicine, University of TCR signaling in vivo by dephosphorylating ZAP-70 and Syk, two Florida, 2033 Mowry Road, Cancer and Genetics Research Complex, Room 430G, key molecules involved in the amplification of TCR-triggered Gainesville, FL 32610 (Y.G.) or Department of Pathology, Immunology and Lab- oratory Medicine, University of Florida, 2033 Mowry Road, Cancer and Genetics signals (2, 25–28). 2 2 Research Complex, Room 115, Gainesville, FL 32610 (P.C.). E-mail addresses: Mice lacking either Ubash3a (Ubash3a / )orUbash3b yange09@ufl.edu (Y.G.) or patcon@ufl.edu (P.C.) (Ubash3b2/2) or both paralogues (Ubash3a2/2Ubash3b2/2) have The online version of this article contains supplemental material. been constructed, but none of these lines exhibit overt defects in Abbreviations used in this article: DAVID, Database for Annotation, Visualization the absence of immune challenge (1). Upon TCR stimulation, and Integrated Discovery; ER, endoplasmic reticulum; ERAD, ER-associated protein 2/2 2/2 degradation; GO, gene ontology; GST, glutathione S-transferase; LC-MS/MS, liquid isolated Ubash3a Ubash3b T cells are hyperproliferative chromatography–tandem mass spectrometry; MFI, median fluorescence intensity; and produce more IL-2 and IFN-g than wild-type T cells, whereas MS/MS, tandem mass spectrometry; NP-40, Nonidet P-40; PGM, phosphoglycerate T cells from Ubash3a2/2 and Ubash3b2/2 single-knockout mice mutase-like; SH3, Src homology 3; T1D, type 1 diabetes; UBA, ubiquitin-associated. display only a modest increase in proliferation (2). Consistent with Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 its negligible phosphatase activity, the knockout of Ubash3a alone www.jimmunol.org/cgi/doi/10.4049/jimmunol.1801338 2 UBASH3A REGULATES THE SYNTHESIS AND DYNAMICS OF TCR–CD3 results in only a slight increase in phosphorylation of ZAP-70 (2). Coimmunoprecipitation and immunoblotting Thus, in mice, although Ubash3a does act, in combination with For coimmunoprecipitation, 0.5–1 mg of lysate was incubated for 4 h or Ubash3b, to suppress T cell signaling, the primary source of the overnight at 4˚C with 1 mg of IgG or the indicated Ab to human CD3ε phosphatase activity for this role is Ubash3b (1–4). (rabbit polyclonal; Santa Cruz Biotechnology), CD3z (clone 6B10.2; Santa We previously reported that UBASH3A attenuates NF-kB Cruz Biotechnology), PSMC4 (clone H-2; Santa Cruz Biotechnology), signaling by inhibiting the activation of the IkB kinase complex. UBASH3A (rabbit polyclonal; MilliporeSigma), or V5 (mouse monoclo- nal; Thermo Fisher Scientific). Next, 20 ml of Protein G Dynabeads This effect is mediated by the UBA and SH3 domains of (Thermo Fisher Scientific) was added and incubated with the lysate for 1 h UBASH3A, demonstrating a phosphatase-independent function at 4˚C. The beads were washed four times with EBC lysis buffer (29), of UBASH3A in T cells (5). We further showed that genetic and the immunoprecipitates were eluted by heating the beads for 10 min at variants in UBASH3A that were associated with risk of type 1 70˚C in 20 ml of LDS sample buffer (Thermo Fisher Scientific) containing diabetes (T1D) acted by increasing the expression of UBASH3A 50 mM DTT. Whole-cell lysates and the immunoprecipitated samples were resolved in human primary T cells, leading to reduced IL-2 production on NuPAGE Tris-Acetate or Bolt Bis-Tris Plus gels (Thermo Fisher Sci- upon TCR stimulation (5, 15). In this study, we report that vari- entific). After transfer to PVDF membranes, immunoblotting was per- ation in UBASH3A expression modulates cell-surface TCR–CD3 formed using the indicated Ab to human CBL-B (clone G-1; Santa Cruz level, suggesting a link between disease-associated genetic vari- Biotechnology), dynamin (clone 41/Dynamin; BD Biosciences), heat shock ants in UBASH3A and TCR-mediated T cell activation.
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