Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response

ABSTRACT Although the pathogen recognition receptor pathways that activate cell-intrinsic antiviral responses are well delineated, less is known about how the host regulates this response to prevent sustained signaling and possible immune-mediated damage. Using a genome-wide CRISPR-Cas9 screening ap...

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Autores principales:	Hongming Ma, Wei Qian, Monika Bambouskova, Patrick L. Collins, Sofia I. Porter, Andrea K. Byrum, Rong Zhang, Maxim Artyomov, Eugene M. Oltz, Nima Mosammaparast, Jonathan J. Miner, Michael S. Diamond
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	interferon-stimulated gene regulation innate immunity CRISPR DNA virus RNA virus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0f2c9b9750b24e7f848a405e26004f91
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spelling	oai:doaj.org-article:0f2c9b9750b24e7f848a405e26004f912021-11-15T15:57:03ZBarrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response10.1128/mBio.00136-202150-7511https://doaj.org/article/0f2c9b9750b24e7f848a405e26004f912020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00136-20https://doaj.org/toc/2150-7511ABSTRACT Although the pathogen recognition receptor pathways that activate cell-intrinsic antiviral responses are well delineated, less is known about how the host regulates this response to prevent sustained signaling and possible immune-mediated damage. Using a genome-wide CRISPR-Cas9 screening approach to identify host factors that modulate interferon-stimulated gene (ISG) expression, we identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1), a previously described inhibitor of retrovirus integration, as a modulator of basal cell-intrinsic immunity. Ablation of Banf1 by gene editing resulted in chromatin activation near host defense genes with associated increased expression of ISGs, including Oas2, Rsad2 (viperin), Ifit1, and ISG15. The phenotype in Banf1-deficient cells occurred through a cGAS-, STING-, and IRF3-dependent signaling axis, was associated with reduced infection of RNA and DNA viruses, and was reversed in Banf1 complemented cells. Confocal microscopy and biochemical studies revealed that a loss of Banf1 expression resulted in higher level of cytosolic double-stranded DNA at baseline. Our study identifies an undescribed role for Banf1 in regulating the levels of cytoplasmic DNA and cGAS-dependent ISG homeostasis and suggests possible therapeutic directions for promoting or inhibiting cell-intrinsic innate immune responses. IMPORTANCE Although the interferon (IFN) signaling pathway is a key host mechanism to restrict infection of a diverse range of viral pathogens, its unrestrained activity either at baseline or in the context of an immune response can result in host cell damage and injury. Here, we used a genome-wide CRISPR-Cas9 screen and identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1) as a modulator of basal cell-intrinsic immunity. A loss of Banf1 expression resulted in higher level of cytosolic double-stranded DNA at baseline, which triggered IFN-stimulated gene expression via a cGAS-STING-IRF3 axis that did not require type I IFN or STAT1 signaling. Our experiments define a regulatory network in which Banf1 limits basal inflammation by preventing self DNA accumulation in the cytosol.Hongming MaWei QianMonika BambouskovaPatrick L. CollinsSofia I. PorterAndrea K. ByrumRong ZhangMaxim ArtyomovEugene M. OltzNima MosammaparastJonathan J. MinerMichael S. DiamondAmerican Society for Microbiologyarticleinterferon-stimulated generegulationinnate immunityCRISPRDNA virusRNA virusMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	interferon-stimulated gene regulation innate immunity CRISPR DNA virus RNA virus Microbiology QR1-502
spellingShingle	interferon-stimulated gene regulation innate immunity CRISPR DNA virus RNA virus Microbiology QR1-502 Hongming Ma Wei Qian Monika Bambouskova Patrick L. Collins Sofia I. Porter Andrea K. Byrum Rong Zhang Maxim Artyomov Eugene M. Oltz Nima Mosammaparast Jonathan J. Miner Michael S. Diamond Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response
description	ABSTRACT Although the pathogen recognition receptor pathways that activate cell-intrinsic antiviral responses are well delineated, less is known about how the host regulates this response to prevent sustained signaling and possible immune-mediated damage. Using a genome-wide CRISPR-Cas9 screening approach to identify host factors that modulate interferon-stimulated gene (ISG) expression, we identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1), a previously described inhibitor of retrovirus integration, as a modulator of basal cell-intrinsic immunity. Ablation of Banf1 by gene editing resulted in chromatin activation near host defense genes with associated increased expression of ISGs, including Oas2, Rsad2 (viperin), Ifit1, and ISG15. The phenotype in Banf1-deficient cells occurred through a cGAS-, STING-, and IRF3-dependent signaling axis, was associated with reduced infection of RNA and DNA viruses, and was reversed in Banf1 complemented cells. Confocal microscopy and biochemical studies revealed that a loss of Banf1 expression resulted in higher level of cytosolic double-stranded DNA at baseline. Our study identifies an undescribed role for Banf1 in regulating the levels of cytoplasmic DNA and cGAS-dependent ISG homeostasis and suggests possible therapeutic directions for promoting or inhibiting cell-intrinsic innate immune responses. IMPORTANCE Although the interferon (IFN) signaling pathway is a key host mechanism to restrict infection of a diverse range of viral pathogens, its unrestrained activity either at baseline or in the context of an immune response can result in host cell damage and injury. Here, we used a genome-wide CRISPR-Cas9 screen and identified the DNA binding protein Barrier-to-autointegration factor 1 (Banf1) as a modulator of basal cell-intrinsic immunity. A loss of Banf1 expression resulted in higher level of cytosolic double-stranded DNA at baseline, which triggered IFN-stimulated gene expression via a cGAS-STING-IRF3 axis that did not require type I IFN or STAT1 signaling. Our experiments define a regulatory network in which Banf1 limits basal inflammation by preventing self DNA accumulation in the cytosol.
format	article
author	Hongming Ma Wei Qian Monika Bambouskova Patrick L. Collins Sofia I. Porter Andrea K. Byrum Rong Zhang Maxim Artyomov Eugene M. Oltz Nima Mosammaparast Jonathan J. Miner Michael S. Diamond
author_facet	Hongming Ma Wei Qian Monika Bambouskova Patrick L. Collins Sofia I. Porter Andrea K. Byrum Rong Zhang Maxim Artyomov Eugene M. Oltz Nima Mosammaparast Jonathan J. Miner Michael S. Diamond
author_sort	Hongming Ma
title	Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response
title_short	Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response
title_full	Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response
title_fullStr	Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response
title_full_unstemmed	Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response
title_sort	barrier-to-autointegration factor 1 protects against a basal cgas-sting response
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/0f2c9b9750b24e7f848a405e26004f91
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Barrier-to-Autointegration Factor 1 Protects against a Basal cGAS-STING Response

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