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

Abstract 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 cir...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Huawei Wang, Chuanlong Zang, Mengtian Ren, Mengdi Shang, Zhenghua Wang, Xuemei Peng, Qiangzhe Zhang, Xin Wen, Zhen Xi, Chuanzheng Zhou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/345f0b8324f74affa56dc279827d5908
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:345f0b8324f74affa56dc279827d5908
record_format	dspace
spelling	oai:doaj.org-article:345f0b8324f74affa56dc279827d59082021-12-02T18:48:08ZCellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS)10.1038/s41598-020-72393-w2045-2322https://doaj.org/article/345f0b8324f74affa56dc279827d59082020-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-72393-whttps://doaj.org/toc/2045-2322Abstract 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.Huawei WangChuanlong ZangMengtian RenMengdi ShangZhenghua WangXuemei PengQiangzhe ZhangXin WenZhen XiChuanzheng ZhouNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Huawei Wang Chuanlong Zang Mengtian Ren Mengdi Shang Zhenghua Wang Xuemei Peng Qiangzhe Zhang Xin Wen Zhen Xi Chuanzheng Zhou Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS)
description	Abstract 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.
format	article
author	Huawei Wang Chuanlong Zang Mengtian Ren Mengdi Shang Zhenghua Wang Xuemei Peng Qiangzhe Zhang Xin Wen Zhen Xi Chuanzheng Zhou
author_facet	Huawei Wang Chuanlong Zang Mengtian Ren Mengdi Shang Zhenghua Wang Xuemei Peng Qiangzhe Zhang Xin Wen Zhen Xi Chuanzheng Zhou
author_sort	Huawei Wang
title	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_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_sort	cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cgmp-amp synthase (cgas)
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/345f0b8324f74affa56dc279827d5908
work_keys_str_mv	AT huaweiwang cellularuptakeofextracellularnucleosomesinducesinnateimmuneresponsesbybindingandactivatingcgmpampsynthasecgas AT chuanlongzang cellularuptakeofextracellularnucleosomesinducesinnateimmuneresponsesbybindingandactivatingcgmpampsynthasecgas AT mengtianren cellularuptakeofextracellularnucleosomesinducesinnateimmuneresponsesbybindingandactivatingcgmpampsynthasecgas AT mengdishang cellularuptakeofextracellularnucleosomesinducesinnateimmuneresponsesbybindingandactivatingcgmpampsynthasecgas AT zhenghuawang cellularuptakeofextracellularnucleosomesinducesinnateimmuneresponsesbybindingandactivatingcgmpampsynthasecgas AT xuemeipeng cellularuptakeofextracellularnucleosomesinducesinnateimmuneresponsesbybindingandactivatingcgmpampsynthasecgas AT qiangzhezhang cellularuptakeofextracellularnucleosomesinducesinnateimmuneresponsesbybindingandactivatingcgmpampsynthasecgas AT xinwen cellularuptakeofextracellularnucleosomesinducesinnateimmuneresponsesbybindingandactivatingcgmpampsynthasecgas AT zhenxi cellularuptakeofextracellularnucleosomesinducesinnateimmuneresponsesbybindingandactivatingcgmpampsynthasecgas AT chuanzhengzhou cellularuptakeofextracellularnucleosomesinducesinnateimmuneresponsesbybindingandactivatingcgmpampsynthasecgas
_version_	1718377615441526784

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

Ejemplares similares