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Tight nuclear tethering of cGAS is essential for preventing autoreactivity

cGAS is an intracellular innate immune sensor that detects double-stranded DNA. The presence of billions of base pairs of genomic DNA in all nucleated cells raises the question of how cGAS is not constitutively activated. A widely accepted explanation for this is the sequestration of cGAS in the cyt...

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Autores principales: Volkman, Hannah E, Cambier, Stephanie, Gray, Elizabeth E, Stetson, Daniel B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927687/
https://www.ncbi.nlm.nih.gov/pubmed/31808743
http://dx.doi.org/10.7554/eLife.47491
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author Volkman, Hannah E
Cambier, Stephanie
Gray, Elizabeth E
Stetson, Daniel B
author_facet Volkman, Hannah E
Cambier, Stephanie
Gray, Elizabeth E
Stetson, Daniel B
author_sort Volkman, Hannah E
collection PubMed
description cGAS is an intracellular innate immune sensor that detects double-stranded DNA. The presence of billions of base pairs of genomic DNA in all nucleated cells raises the question of how cGAS is not constitutively activated. A widely accepted explanation for this is the sequestration of cGAS in the cytosol, which is thought to prevent cGAS from accessing nuclear DNA. Here, we demonstrate that endogenous cGAS is predominantly a nuclear protein, regardless of cell cycle phase or cGAS activation status. We show that nuclear cGAS is tethered tightly by a salt-resistant interaction. This tight tethering is independent of the domains required for cGAS activation, and it requires intact nuclear chromatin. We identify the evolutionarily conserved tethering surface on cGAS and we show that mutation of single amino acids within this surface renders cGAS massively and constitutively active against self-DNA. Thus, tight nuclear tethering maintains the resting state of cGAS and prevents autoreactivity.
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spelling pubmed-69276872019-12-26 Tight nuclear tethering of cGAS is essential for preventing autoreactivity Volkman, Hannah E Cambier, Stephanie Gray, Elizabeth E Stetson, Daniel B eLife Immunology and Inflammation cGAS is an intracellular innate immune sensor that detects double-stranded DNA. The presence of billions of base pairs of genomic DNA in all nucleated cells raises the question of how cGAS is not constitutively activated. A widely accepted explanation for this is the sequestration of cGAS in the cytosol, which is thought to prevent cGAS from accessing nuclear DNA. Here, we demonstrate that endogenous cGAS is predominantly a nuclear protein, regardless of cell cycle phase or cGAS activation status. We show that nuclear cGAS is tethered tightly by a salt-resistant interaction. This tight tethering is independent of the domains required for cGAS activation, and it requires intact nuclear chromatin. We identify the evolutionarily conserved tethering surface on cGAS and we show that mutation of single amino acids within this surface renders cGAS massively and constitutively active against self-DNA. Thus, tight nuclear tethering maintains the resting state of cGAS and prevents autoreactivity. eLife Sciences Publications, Ltd 2019-12-06 /pmc/articles/PMC6927687/ /pubmed/31808743 http://dx.doi.org/10.7554/eLife.47491 Text en © 2019, Volkman et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Volkman, Hannah E
Cambier, Stephanie
Gray, Elizabeth E
Stetson, Daniel B
Tight nuclear tethering of cGAS is essential for preventing autoreactivity
title Tight nuclear tethering of cGAS is essential for preventing autoreactivity
title_full Tight nuclear tethering of cGAS is essential for preventing autoreactivity
title_fullStr Tight nuclear tethering of cGAS is essential for preventing autoreactivity
title_full_unstemmed Tight nuclear tethering of cGAS is essential for preventing autoreactivity
title_short Tight nuclear tethering of cGAS is essential for preventing autoreactivity
title_sort tight nuclear tethering of cgas is essential for preventing autoreactivity
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927687/
https://www.ncbi.nlm.nih.gov/pubmed/31808743
http://dx.doi.org/10.7554/eLife.47491
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