Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway

ABSTRACT High-risk human papillomaviruses (HPVs) constitutively activate the ataxia telangiectasia and Rad3-related (ATR) DNA damage response pathway, and this is required for viral replication. In fibroblasts, activated ATR regulates transcription of inflammatory genes through its negative effects...

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Autores principales:	Shiyuan Hong, Yan Li, Paul J. Kaminski, Jorge Andrade, Laimonis A. Laimins
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	DNA replication GATA4 HPV inflammation interferons p62 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5d0cf5180f0043dbaf1cd79c8ed96a12
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spelling	oai:doaj.org-article:5d0cf5180f0043dbaf1cd79c8ed96a122021-11-15T15:56:44ZPathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway10.1128/mBio.01628-202150-7511https://doaj.org/article/5d0cf5180f0043dbaf1cd79c8ed96a122020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01628-20https://doaj.org/toc/2150-7511ABSTRACT High-risk human papillomaviruses (HPVs) constitutively activate the ataxia telangiectasia and Rad3-related (ATR) DNA damage response pathway, and this is required for viral replication. In fibroblasts, activated ATR regulates transcription of inflammatory genes through its negative effects on the autophagosome cargo protein p62. In addition, suppression of p62 results in increased levels of the transcription factor GATA4, leading to cellular senescence. In contrast, in HPV-positive keratinocytes, we observed that activation of ATR resulted in increased levels of phosphorylated p62, which in turn lead to reduced levels of GATA4. Knockdown of ATR in HPV-positive cells resulted in decreased p62 phosphorylation and increased GATA4 levels. Transcriptome sequencing (RNA-seq) analysis of HPV-positive cells identified inflammatory genes and interferon factors as negative transcriptional targets of ATR. Furthermore, knockdown of p62 or overexpression of GATA4 in HPV-positive cells leads to inhibition of viral replication. These findings identify a novel role of the ATR/p62 signaling pathway in HPV-positive cells. IMPORTANCE High-risk human papillomaviruses (HPVs) infect epithelial cells and induce viral genome amplification upon differentiation. HPV proteins activate the ATR DNA damage repair pathway, and this is required for HPV genome amplification. In the present study, we show that HPV-induced ATR activation also leads to suppression of expression of inflammatory response genes. This suppression results from HPV-induced phosphorylation of the autophagosome cargo protein p62 which regulates the levels of the transcription factor GATA4. Activation of p62 in normal fibroblasts results in senescence, but this is not seen in HPV-positive keratinocytes. Importantly, knockdown of p62 or overexpression of GATA4 in HPV-positive cells abrogates viral replication. This study demonstrates that activation of ATR in HPV-positive cells triggers a p62-directed pathway inducing suppression of inflammatory gene expression independent of DNA repair and facilitating HPV replication.Shiyuan HongYan LiPaul J. KaminskiJorge AndradeLaimonis A. LaiminsAmerican Society for MicrobiologyarticleDNA replicationGATA4HPVinflammationinterferonsp62MicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	DNA replication GATA4 HPV inflammation interferons p62 Microbiology QR1-502
spellingShingle	DNA replication GATA4 HPV inflammation interferons p62 Microbiology QR1-502 Shiyuan Hong Yan Li Paul J. Kaminski Jorge Andrade Laimonis A. Laimins Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway
description	ABSTRACT High-risk human papillomaviruses (HPVs) constitutively activate the ataxia telangiectasia and Rad3-related (ATR) DNA damage response pathway, and this is required for viral replication. In fibroblasts, activated ATR regulates transcription of inflammatory genes through its negative effects on the autophagosome cargo protein p62. In addition, suppression of p62 results in increased levels of the transcription factor GATA4, leading to cellular senescence. In contrast, in HPV-positive keratinocytes, we observed that activation of ATR resulted in increased levels of phosphorylated p62, which in turn lead to reduced levels of GATA4. Knockdown of ATR in HPV-positive cells resulted in decreased p62 phosphorylation and increased GATA4 levels. Transcriptome sequencing (RNA-seq) analysis of HPV-positive cells identified inflammatory genes and interferon factors as negative transcriptional targets of ATR. Furthermore, knockdown of p62 or overexpression of GATA4 in HPV-positive cells leads to inhibition of viral replication. These findings identify a novel role of the ATR/p62 signaling pathway in HPV-positive cells. IMPORTANCE High-risk human papillomaviruses (HPVs) infect epithelial cells and induce viral genome amplification upon differentiation. HPV proteins activate the ATR DNA damage repair pathway, and this is required for HPV genome amplification. In the present study, we show that HPV-induced ATR activation also leads to suppression of expression of inflammatory response genes. This suppression results from HPV-induced phosphorylation of the autophagosome cargo protein p62 which regulates the levels of the transcription factor GATA4. Activation of p62 in normal fibroblasts results in senescence, but this is not seen in HPV-positive keratinocytes. Importantly, knockdown of p62 or overexpression of GATA4 in HPV-positive cells abrogates viral replication. This study demonstrates that activation of ATR in HPV-positive cells triggers a p62-directed pathway inducing suppression of inflammatory gene expression independent of DNA repair and facilitating HPV replication.
format	article
author	Shiyuan Hong Yan Li Paul J. Kaminski Jorge Andrade Laimonis A. Laimins
author_facet	Shiyuan Hong Yan Li Paul J. Kaminski Jorge Andrade Laimonis A. Laimins
author_sort	Shiyuan Hong
title	Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway
title_short	Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway
title_full	Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway
title_fullStr	Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway
title_full_unstemmed	Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway
title_sort	pathogenesis of human papillomaviruses requires the atr/p62 autophagy-related pathway
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/5d0cf5180f0043dbaf1cd79c8ed96a12
work_keys_str_mv	AT shiyuanhong pathogenesisofhumanpapillomavirusesrequirestheatrp62autophagyrelatedpathway AT yanli pathogenesisofhumanpapillomavirusesrequirestheatrp62autophagyrelatedpathway AT pauljkaminski pathogenesisofhumanpapillomavirusesrequirestheatrp62autophagyrelatedpathway AT jorgeandrade pathogenesisofhumanpapillomavirusesrequirestheatrp62autophagyrelatedpathway AT laimonisalaimins pathogenesisofhumanpapillomavirusesrequirestheatrp62autophagyrelatedpathway
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Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway

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