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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...

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Autores principales: Yan, Qiongyu, Zhang, Bin, Ling, Xi, Zhu, Bin, Mei, Shenghui, Yang, Hua, Zhang, Dongjie, Huo, Jiping, Zhao, Zhigang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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.
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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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