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CTLA-4 Facilitates DNA Damage–Induced Apoptosis by Interacting With PP2A
Cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) plays a pivotal role in regulating immune responses. It accumulates in intracellular compartments, translocates to the cell surface, and is rapidly internalized. However, the cytoplasmic function of CTLA-4 remains largely unknown. Here, we describ...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8907142/ https://www.ncbi.nlm.nih.gov/pubmed/35281086 http://dx.doi.org/10.3389/fcell.2022.728771 |
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author | Yan, Qiongyu Zhang, Bin Ling, Xi Zhu, Bin Mei, Shenghui Yang, Hua Zhang, Dongjie Huo, Jiping Zhao, Zhigang |
author_facet | Yan, Qiongyu Zhang, Bin Ling, Xi Zhu, Bin Mei, Shenghui Yang, Hua Zhang, Dongjie Huo, Jiping Zhao, Zhigang |
author_sort | Yan, Qiongyu |
collection | PubMed |
description | Cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) plays a pivotal role in regulating immune responses. It accumulates in intracellular compartments, translocates to the cell surface, and is rapidly internalized. However, the cytoplasmic function of CTLA-4 remains largely unknown. Here, we describe the role of CTLA-4 as an immunomodulator in the DNA damage response to genotoxic stress. Using isogenic models of murine T cells with either sufficient or deficient CTLA-4 expression and performing a variety of assays, including cell apoptosis, cell cycle, comet, western blotting, co-immunoprecipitation, and immunofluorescence staining analyses, we show that CTLA-4 activates ataxia–telangiectasia mutated (ATM) by binding to the ATM inhibitor protein phosphatase 2A into the cytoplasm of T cells following transient treatment with zeocin, exacerbating the DNA damage response and inducing apoptosis. These findings provide new insights into how T cells maintain their immune function under high-stress conditions, which is clinically important for patients with tumors undergoing immunotherapy combined with chemoradiotherapy. |
format | Online Article Text |
id | pubmed-8907142 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89071422022-03-11 CTLA-4 Facilitates DNA Damage–Induced Apoptosis by Interacting With PP2A Yan, Qiongyu Zhang, Bin Ling, Xi Zhu, Bin Mei, Shenghui Yang, Hua Zhang, Dongjie Huo, Jiping Zhao, Zhigang Front Cell Dev Biol Cell and Developmental Biology Cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) plays a pivotal role in regulating immune responses. It accumulates in intracellular compartments, translocates to the cell surface, and is rapidly internalized. However, the cytoplasmic function of CTLA-4 remains largely unknown. Here, we describe the role of CTLA-4 as an immunomodulator in the DNA damage response to genotoxic stress. Using isogenic models of murine T cells with either sufficient or deficient CTLA-4 expression and performing a variety of assays, including cell apoptosis, cell cycle, comet, western blotting, co-immunoprecipitation, and immunofluorescence staining analyses, we show that CTLA-4 activates ataxia–telangiectasia mutated (ATM) by binding to the ATM inhibitor protein phosphatase 2A into the cytoplasm of T cells following transient treatment with zeocin, exacerbating the DNA damage response and inducing apoptosis. These findings provide new insights into how T cells maintain their immune function under high-stress conditions, which is clinically important for patients with tumors undergoing immunotherapy combined with chemoradiotherapy. Frontiers Media S.A. 2022-02-24 /pmc/articles/PMC8907142/ /pubmed/35281086 http://dx.doi.org/10.3389/fcell.2022.728771 Text en Copyright © 2022 Yan, Zhang, Ling, Zhu, Mei, Yang, Zhang, Huo and Zhao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Yan, Qiongyu Zhang, Bin Ling, Xi Zhu, Bin Mei, Shenghui Yang, Hua Zhang, Dongjie Huo, Jiping Zhao, Zhigang CTLA-4 Facilitates DNA Damage–Induced Apoptosis by Interacting With PP2A |
title | CTLA-4 Facilitates DNA Damage–Induced Apoptosis by Interacting With PP2A |
title_full | CTLA-4 Facilitates DNA Damage–Induced Apoptosis by Interacting With PP2A |
title_fullStr | CTLA-4 Facilitates DNA Damage–Induced Apoptosis by Interacting With PP2A |
title_full_unstemmed | CTLA-4 Facilitates DNA Damage–Induced Apoptosis by Interacting With PP2A |
title_short | CTLA-4 Facilitates DNA Damage–Induced Apoptosis by Interacting With PP2A |
title_sort | ctla-4 facilitates dna damage–induced apoptosis by interacting with pp2a |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8907142/ https://www.ncbi.nlm.nih.gov/pubmed/35281086 http://dx.doi.org/10.3389/fcell.2022.728771 |
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