UBASH3A Regulates the Synthesis and Dynamics of TCR-CD3 Complexes
Copyright © 2019 by The American Association of Immunologists, Inc..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:203 |
|---|---|
| Enthalten in: |
Journal of immunology (Baltimore, Md. : 1950) - 203(2019), 11 vom: 01. Dez., Seite 2827-2836 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ge, Yan [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Adaptor Proteins, Signal Transducing |
|---|
| Anmerkungen: |
Date Completed 27.05.2020 Date Revised 01.12.2020 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.4049/jimmunol.1801338 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM302637362 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM302637362 | ||
| 003 | DE-627 | ||
| 005 | 20231225111135.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.4049/jimmunol.1801338 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1008.xml |
| 035 | |a (DE-627)NLM302637362 | ||
| 035 | |a (NLM)31659016 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Ge, Yan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a UBASH3A Regulates the Synthesis and Dynamics of TCR-CD3 Complexes |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 27.05.2020 | ||
| 500 | |a Date Revised 01.12.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 by The American Association of Immunologists, Inc. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
| 650 | 7 | |a CD3 Complex |2 NLM | |
| 650 | 7 | |a Receptors, Antigen, T-Cell |2 NLM | |
| 650 | 7 | |a UBASH3A protein, human |2 NLM | |
| 700 | 1 | |a Paisie, Taylor K |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Sixue |e verfasserin |4 aut | |
| 700 | 1 | |a Concannon, Patrick |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of immunology (Baltimore, Md. : 1950) |d 1945 |g 203(2019), 11 vom: 01. Dez., Seite 2827-2836 |w (DE-627)NLM000018554 |x 1550-6606 |7 nnns |
| 773 | 1 | 8 | |g volume:203 |g year:2019 |g number:11 |g day:01 |g month:12 |g pages:2827-2836 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.4049/jimmunol.1801338 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 203 |j 2019 |e 11 |b 01 |c 12 |h 2827-2836 | ||