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Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection
T cells play a crucial role in viral clearance and vaccine responses; however, the mechanisms that regulate their homeostasis during viral infections remain unclear. In this study, we investigated the machineries of T-cell homeostasis and telomeric DNA damage using a human model of hepatitis C virus...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125360/ https://www.ncbi.nlm.nih.gov/pubmed/30185784 http://dx.doi.org/10.1038/s41419-018-0897-y |
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author | Nguyen, Lam Nhat Zhao, Juan Cao, Dechao Dang, Xindi Wang, Ling Lian, Jianqi Zhang, Ying Jia, Zhansheng Wu, Xiao Y. Morrison, Zheng Xie, Qian Ji, Yingjie Zhang, Zheng El Gazzar, Mohamed Ning, Shunbin Moorman, Jonathan P. Yao, Zhi Q. |
author_facet | Nguyen, Lam Nhat Zhao, Juan Cao, Dechao Dang, Xindi Wang, Ling Lian, Jianqi Zhang, Ying Jia, Zhansheng Wu, Xiao Y. Morrison, Zheng Xie, Qian Ji, Yingjie Zhang, Zheng El Gazzar, Mohamed Ning, Shunbin Moorman, Jonathan P. Yao, Zhi Q. |
author_sort | Nguyen, Lam Nhat |
collection | PubMed |
description | T cells play a crucial role in viral clearance and vaccine responses; however, the mechanisms that regulate their homeostasis during viral infections remain unclear. In this study, we investigated the machineries of T-cell homeostasis and telomeric DNA damage using a human model of hepatitis C virus (HCV) infection. We found that naïve CD4 T cells in chronically HCV-infected patients (HCV T cells) were significantly reduced due to apoptosis compared with age-matched healthy subjects (HSs). These HCV T cells were not only senescent, as demonstrated by overexpression of aging markers and particularly shortened telomeres; but also DNA damaged, as evidenced by increased dysfunctional telomere-induced foci (TIF). Mechanistically, the telomere shelterin protein, in particular telomeric repeat binding factor 2 (TRF2) that functions to protect telomeres from DNA damage, was significantly inhibited posttranscriptionally via the p53-dependent Siah-1a ubiquitination. Importantly, knockdown of TRF2 in healthy T cells resulted in increases in telomeric DNA damage and T-cell apoptosis, whereas overexpression of TRF2 in HCV T cells alleviated telomeric DNA damage and T-cell apoptosis. To the best of our knowledge, this is the first report revealing that inhibition of TRF2 promotes T-cell telomere attrition and telomeric DNA damage that accelerates T-cell senescent and apoptotic programs, which contribute to naïve T-cell loss during viral infection. Thus, restoring the impaired T-cell telomeric shelterin machinery may offer a new strategy to improve immunotherapy and vaccine response against human viral diseases. |
format | Online Article Text |
id | pubmed-6125360 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-61253602018-09-06 Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection Nguyen, Lam Nhat Zhao, Juan Cao, Dechao Dang, Xindi Wang, Ling Lian, Jianqi Zhang, Ying Jia, Zhansheng Wu, Xiao Y. Morrison, Zheng Xie, Qian Ji, Yingjie Zhang, Zheng El Gazzar, Mohamed Ning, Shunbin Moorman, Jonathan P. Yao, Zhi Q. Cell Death Dis Article T cells play a crucial role in viral clearance and vaccine responses; however, the mechanisms that regulate their homeostasis during viral infections remain unclear. In this study, we investigated the machineries of T-cell homeostasis and telomeric DNA damage using a human model of hepatitis C virus (HCV) infection. We found that naïve CD4 T cells in chronically HCV-infected patients (HCV T cells) were significantly reduced due to apoptosis compared with age-matched healthy subjects (HSs). These HCV T cells were not only senescent, as demonstrated by overexpression of aging markers and particularly shortened telomeres; but also DNA damaged, as evidenced by increased dysfunctional telomere-induced foci (TIF). Mechanistically, the telomere shelterin protein, in particular telomeric repeat binding factor 2 (TRF2) that functions to protect telomeres from DNA damage, was significantly inhibited posttranscriptionally via the p53-dependent Siah-1a ubiquitination. Importantly, knockdown of TRF2 in healthy T cells resulted in increases in telomeric DNA damage and T-cell apoptosis, whereas overexpression of TRF2 in HCV T cells alleviated telomeric DNA damage and T-cell apoptosis. To the best of our knowledge, this is the first report revealing that inhibition of TRF2 promotes T-cell telomere attrition and telomeric DNA damage that accelerates T-cell senescent and apoptotic programs, which contribute to naïve T-cell loss during viral infection. Thus, restoring the impaired T-cell telomeric shelterin machinery may offer a new strategy to improve immunotherapy and vaccine response against human viral diseases. Nature Publishing Group UK 2018-09-05 /pmc/articles/PMC6125360/ /pubmed/30185784 http://dx.doi.org/10.1038/s41419-018-0897-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Nguyen, Lam Nhat Zhao, Juan Cao, Dechao Dang, Xindi Wang, Ling Lian, Jianqi Zhang, Ying Jia, Zhansheng Wu, Xiao Y. Morrison, Zheng Xie, Qian Ji, Yingjie Zhang, Zheng El Gazzar, Mohamed Ning, Shunbin Moorman, Jonathan P. Yao, Zhi Q. Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection |
title | Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection |
title_full | Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection |
title_fullStr | Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection |
title_full_unstemmed | Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection |
title_short | Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection |
title_sort | inhibition of trf2 accelerates telomere attrition and dna damage in naïve cd4 t cells during hcv infection |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125360/ https://www.ncbi.nlm.nih.gov/pubmed/30185784 http://dx.doi.org/10.1038/s41419-018-0897-y |
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