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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2020-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01628-20 |
| _version_ | 1819203089909940224 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-23T04:14:23Z |
| format | Article |
| id | doaj.art-5d0cf5180f0043dbaf1cd79c8ed96a12 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-23T04:14:23Z |
| publishDate | 2020-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-5d0cf5180f0043dbaf1cd79c8ed96a122022-12-21T18:00:24ZengAmerican Society for MicrobiologymBio2150-75112020-08-0111410.1128/mBio.01628-20Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related PathwayShiyuan Hong0Yan Li1Paul J. Kaminski2Jorge Andrade3Laimonis A. Laimins4Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USACenter for Research Informatics, The University of Chicago, Chicago, Illinois, USADepartment of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USACenter for Research Informatics, The University of Chicago, Chicago, Illinois, USADepartment of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.01628-20DNA replicationGATA4HPVinflammationinterferonsp62 |
| spellingShingle | Shiyuan Hong Yan Li Paul J. Kaminski Jorge Andrade Laimonis A. Laimins Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway mBio DNA replication GATA4 HPV inflammation interferons p62 |
| title | 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_short | Pathogenesis of Human Papillomaviruses Requires the ATR/p62 Autophagy-Related Pathway |
| title_sort | pathogenesis of human papillomaviruses requires the atr p62 autophagy related pathway |
| topic | DNA replication GATA4 HPV inflammation interferons p62 |
| url | https://journals.asm.org/doi/10.1128/mBio.01628-20 |
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