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Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS)

The nucleosome is the basic structural repeating unit of chromatin. DNA damage and cell apoptosis release nucleosomes into the blood circulatory system, and increased levels of circulating nucleosomes have been observed to be related to inflammation and autoimmune diseases. However, how circulating...

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Autores principales: Wang, Huawei, Zang, Chuanlong, Ren, Mengtian, Shang, Mengdi, Wang, Zhenghua, Peng, Xuemei, Zhang, Qiangzhe, Wen, Xin, Xi, Zhen, Zhou, Chuanzheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505961/
https://www.ncbi.nlm.nih.gov/pubmed/32958884
http://dx.doi.org/10.1038/s41598-020-72393-w
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author Wang, Huawei
Zang, Chuanlong
Ren, Mengtian
Shang, Mengdi
Wang, Zhenghua
Peng, Xuemei
Zhang, Qiangzhe
Wen, Xin
Xi, Zhen
Zhou, Chuanzheng
author_facet Wang, Huawei
Zang, Chuanlong
Ren, Mengtian
Shang, Mengdi
Wang, Zhenghua
Peng, Xuemei
Zhang, Qiangzhe
Wen, Xin
Xi, Zhen
Zhou, Chuanzheng
author_sort Wang, Huawei
collection PubMed
description The nucleosome is the basic structural repeating unit of chromatin. DNA damage and cell apoptosis release nucleosomes into the blood circulatory system, and increased levels of circulating nucleosomes have been observed to be related to inflammation and autoimmune diseases. However, how circulating nucleosomes trigger immune responses has not been fully elucidated. cGAS (cGMP-AMP synthase) is a recently discovered pattern recognition receptor that senses cytoplasmic double-stranded DNA (dsDNA). In this study, we employed in vitro reconstituted nucleosomes to examine whether extracellular nucleosomes can gain access to the cytoplasm of mammalian cells to induce immune responses by activating cGAS. We showed that nucleosomes can be taken up by various mammalian cells. Additionally, we found that in vitro reconstituted mononucleosomes and oligonucleosomes can be recognized by cGAS. Compared to dsDNA, nucleosomes exhibit higher binding affinities to cGAS but considerably lower potency in cGAS activation. Incubation of monocytic cells with reconstituted nucleosomes leads to limited production of type I interferons and proinflammatory cytokines via a cGAS-dependent mechanism. This proof-of-concept study reveals the cGAS-dependent immunogenicity of nucleosomes and highlights the potential roles of circulating nucleosomes in autoimmune diseases, inflammation, and antitumour immunity.
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spelling pubmed-75059612020-09-22 Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS) Wang, Huawei Zang, Chuanlong Ren, Mengtian Shang, Mengdi Wang, Zhenghua Peng, Xuemei Zhang, Qiangzhe Wen, Xin Xi, Zhen Zhou, Chuanzheng Sci Rep Article The nucleosome is the basic structural repeating unit of chromatin. DNA damage and cell apoptosis release nucleosomes into the blood circulatory system, and increased levels of circulating nucleosomes have been observed to be related to inflammation and autoimmune diseases. However, how circulating nucleosomes trigger immune responses has not been fully elucidated. cGAS (cGMP-AMP synthase) is a recently discovered pattern recognition receptor that senses cytoplasmic double-stranded DNA (dsDNA). In this study, we employed in vitro reconstituted nucleosomes to examine whether extracellular nucleosomes can gain access to the cytoplasm of mammalian cells to induce immune responses by activating cGAS. We showed that nucleosomes can be taken up by various mammalian cells. Additionally, we found that in vitro reconstituted mononucleosomes and oligonucleosomes can be recognized by cGAS. Compared to dsDNA, nucleosomes exhibit higher binding affinities to cGAS but considerably lower potency in cGAS activation. Incubation of monocytic cells with reconstituted nucleosomes leads to limited production of type I interferons and proinflammatory cytokines via a cGAS-dependent mechanism. This proof-of-concept study reveals the cGAS-dependent immunogenicity of nucleosomes and highlights the potential roles of circulating nucleosomes in autoimmune diseases, inflammation, and antitumour immunity. Nature Publishing Group UK 2020-09-21 /pmc/articles/PMC7505961/ /pubmed/32958884 http://dx.doi.org/10.1038/s41598-020-72393-w Text en © The Author(s) 2020 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wang, Huawei
Zang, Chuanlong
Ren, Mengtian
Shang, Mengdi
Wang, Zhenghua
Peng, Xuemei
Zhang, Qiangzhe
Wen, Xin
Xi, Zhen
Zhou, Chuanzheng
Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS)
title Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS)
title_full Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS)
title_fullStr Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS)
title_full_unstemmed Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS)
title_short Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS)
title_sort cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cgmp-amp synthase (cgas)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505961/
https://www.ncbi.nlm.nih.gov/pubmed/32958884
http://dx.doi.org/10.1038/s41598-020-72393-w
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