β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein
The cGAS/STING-mediated DNA-sensing signaling pathway is crucial for interferon (IFN) production and host antiviral responses. Herpes simplex virus I (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. Here, we demonstrate that the highly conserved β-catenin p...
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description | The cGAS/STING-mediated DNA-sensing signaling pathway is crucial for interferon (IFN) production and host antiviral responses. Herpes simplex virus I (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. Here, we demonstrate that the highly conserved β-catenin protein in the Wnt signaling pathway is an important factor to enhance the transcription of type I interferon (IFN-I) in the cGAS/STING signaling pathway, and the production of IFN-I mediated by β-catenin was antagonized by HSV-1 US3 protein via its kinase activity. Infection by US3-deficienct HSV-1 and its kinase-dead variants failed to downregulate IFN-I and IFN-stimulated gene (ISG) production induced by β-catenin. Consistent with this, absence of β-catenin enhanced the replication of US3-deficienct HSV-1, but not wild-type HSV-1. The underlying mechanism was the interaction of US3 with β-catenin and its hyperphosphorylation of β-catenin at Thr556 to block its nuclear translocation. For the first time, HSV-1 US3 has been shown to inhibit IFN-I production through hyperphosphorylation of β-catenin and to subvert host antiviral innate immunity.
Although increasing evidence has demonstrated that HSV-1 subverts host immune responses and establishes lifelong latent infection, the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity, especially the cGAS/STING-mediated cellular DNA-sensing signaling pathway, have not been fully explored. Here, we show that β-catenin promotes cGAS/STING-mediated activation of the IFN pathway, which is important for cellular innate immune responses and intrinsic resistance to DNA virus infection. The protein kinase US3 antagonizes the production of IFN by targeting β-catenin via its kinase activity. The findings in this study reveal a novel mechanism for HSV-1 to evade host antiviral immunity and add new knowledge to help in understanding the interaction between the host and HSV-1 infection. |
doi_str_mv | 10.1128/JVI.01847-19 |
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Although increasing evidence has demonstrated that HSV-1 subverts host immune responses and establishes lifelong latent infection, the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity, especially the cGAS/STING-mediated cellular DNA-sensing signaling pathway, have not been fully explored. Here, we show that β-catenin promotes cGAS/STING-mediated activation of the IFN pathway, which is important for cellular innate immune responses and intrinsic resistance to DNA virus infection. The protein kinase US3 antagonizes the production of IFN by targeting β-catenin via its kinase activity. The findings in this study reveal a novel mechanism for HSV-1 to evade host antiviral immunity and add new knowledge to help in understanding the interaction between the host and HSV-1 infection.</description><identifier>ISSN: 0022-538X</identifier><identifier>EISSN: 1098-5514</identifier><identifier>DOI: 10.1128/JVI.01847-19</identifier><identifier>PMID: 31801859</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject>A549 Cells ; Animals ; beta Catenin - genetics ; beta Catenin - metabolism ; Chlorocebus aethiops ; Cytokines ; Down-Regulation ; Gene Knockout Techniques ; HEK293 Cells ; Herpesvirus 1, Human - metabolism ; Humans ; Immunity, Innate ; Interferon Type I - metabolism ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Nucleotidyltransferases - genetics ; Nucleotidyltransferases - metabolism ; Phosphorylation ; Protein Serine-Threonine Kinases - metabolism ; Signal Transduction ; Spotlight ; Vero Cells ; Viral Proteins - metabolism ; Virus-Cell Interactions</subject><ispartof>Journal of virology, 2020-02, Vol.94 (5)</ispartof><rights>Copyright © 2020 American Society for Microbiology.</rights><rights>Copyright © 2020 American Society for Microbiology. 2020 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c427t-8b2500d27578344d6198324d71d326401a67e988cf101e83b10be3c92d49a4253</citedby><cites>FETCH-LOGICAL-c427t-8b2500d27578344d6198324d71d326401a67e988cf101e83b10be3c92d49a4253</cites><orcidid>0000-0002-8797-1322</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022340/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022340/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31801859$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Sandri-Goldin, Rozanne M.</contributor><creatorcontrib>You, Hongjuan</creatorcontrib><creatorcontrib>Lin, Yingying</creatorcontrib><creatorcontrib>Lin, Feng</creatorcontrib><creatorcontrib>Yang, Mingyue</creatorcontrib><creatorcontrib>Li, Jiahui</creatorcontrib><creatorcontrib>Zhang, Rongzhao</creatorcontrib><creatorcontrib>Huang, Zhiming</creatorcontrib><creatorcontrib>Shen, Qingtang</creatorcontrib><creatorcontrib>Tang, Renxian</creatorcontrib><creatorcontrib>Zheng, Chunfu</creatorcontrib><title>β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein</title><title>Journal of virology</title><addtitle>J Virol</addtitle><description>The cGAS/STING-mediated DNA-sensing signaling pathway is crucial for interferon (IFN) production and host antiviral responses. Herpes simplex virus I (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. Here, we demonstrate that the highly conserved β-catenin protein in the Wnt signaling pathway is an important factor to enhance the transcription of type I interferon (IFN-I) in the cGAS/STING signaling pathway, and the production of IFN-I mediated by β-catenin was antagonized by HSV-1 US3 protein via its kinase activity. Infection by US3-deficienct HSV-1 and its kinase-dead variants failed to downregulate IFN-I and IFN-stimulated gene (ISG) production induced by β-catenin. Consistent with this, absence of β-catenin enhanced the replication of US3-deficienct HSV-1, but not wild-type HSV-1. The underlying mechanism was the interaction of US3 with β-catenin and its hyperphosphorylation of β-catenin at Thr556 to block its nuclear translocation. For the first time, HSV-1 US3 has been shown to inhibit IFN-I production through hyperphosphorylation of β-catenin and to subvert host antiviral innate immunity.
Although increasing evidence has demonstrated that HSV-1 subverts host immune responses and establishes lifelong latent infection, the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity, especially the cGAS/STING-mediated cellular DNA-sensing signaling pathway, have not been fully explored. Here, we show that β-catenin promotes cGAS/STING-mediated activation of the IFN pathway, which is important for cellular innate immune responses and intrinsic resistance to DNA virus infection. The protein kinase US3 antagonizes the production of IFN by targeting β-catenin via its kinase activity. The findings in this study reveal a novel mechanism for HSV-1 to evade host antiviral immunity and add new knowledge to help in understanding the interaction between the host and HSV-1 infection.</description><subject>A549 Cells</subject><subject>Animals</subject><subject>beta Catenin - genetics</subject><subject>beta Catenin - metabolism</subject><subject>Chlorocebus aethiops</subject><subject>Cytokines</subject><subject>Down-Regulation</subject><subject>Gene Knockout Techniques</subject><subject>HEK293 Cells</subject><subject>Herpesvirus 1, Human - metabolism</subject><subject>Humans</subject><subject>Immunity, Innate</subject><subject>Interferon Type I - metabolism</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Nucleotidyltransferases - genetics</subject><subject>Nucleotidyltransferases - metabolism</subject><subject>Phosphorylation</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Signal Transduction</subject><subject>Spotlight</subject><subject>Vero Cells</subject><subject>Viral Proteins - metabolism</subject><subject>Virus-Cell Interactions</subject><issn>0022-538X</issn><issn>1098-5514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkctO4zAUhi3ECMplxxp5yYKAj-00zgapqqB0hAZEAbGznOS0NUqdYjswnceaB5lnmnAVrLw43_8f63yE7AE7AuDq-Ofd-IiBklkC-RrpActVkqYg10mPMc6TVKj7TbIVwgNjIGVfbpBNAaqLpHmPtP_-JkMT0VlHx4Fe42NrPVZ02nga50jL0WByPLkZ_xrRiZ05U1s3o1cmzp_NihZtpAMXzaxx9k8XKlavmXP0Swwdv1jW-JveWd8GCvR2IuiVbyJat0N-TE0dcPf93Sa3Z6c3w_Pk4nI0Hg4uklLyLCaq4CljFc_STAkpqz7kSnBZZVAJ3pcMTD_DXKlyCgxQiQJYgaLMeSVzI3kqtsnJW--yLRZYleiiN7VeerswfqUbY_X3ibNzPWuedNZdTkjWFRy8F_jmscUQ9cKGEuvaOGzaoLngHCRX4gU9fENL34Tgcfq5Bph-MaU7U_rVlIa8w_e_fu0T_lAj_gMQBY3b</recordid><startdate>20200214</startdate><enddate>20200214</enddate><creator>You, Hongjuan</creator><creator>Lin, Yingying</creator><creator>Lin, Feng</creator><creator>Yang, Mingyue</creator><creator>Li, Jiahui</creator><creator>Zhang, Rongzhao</creator><creator>Huang, Zhiming</creator><creator>Shen, Qingtang</creator><creator>Tang, Renxian</creator><creator>Zheng, Chunfu</creator><general>American Society for Microbiology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8797-1322</orcidid></search><sort><creationdate>20200214</creationdate><title>β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein</title><author>You, Hongjuan ; Lin, Yingying ; Lin, Feng ; Yang, Mingyue ; Li, Jiahui ; Zhang, Rongzhao ; Huang, Zhiming ; Shen, Qingtang ; Tang, Renxian ; Zheng, Chunfu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c427t-8b2500d27578344d6198324d71d326401a67e988cf101e83b10be3c92d49a4253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>A549 Cells</topic><topic>Animals</topic><topic>beta Catenin - genetics</topic><topic>beta Catenin - metabolism</topic><topic>Chlorocebus aethiops</topic><topic>Cytokines</topic><topic>Down-Regulation</topic><topic>Gene Knockout Techniques</topic><topic>HEK293 Cells</topic><topic>Herpesvirus 1, Human - metabolism</topic><topic>Humans</topic><topic>Immunity, Innate</topic><topic>Interferon Type I - metabolism</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Nucleotidyltransferases - genetics</topic><topic>Nucleotidyltransferases - metabolism</topic><topic>Phosphorylation</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Signal Transduction</topic><topic>Spotlight</topic><topic>Vero Cells</topic><topic>Viral Proteins - metabolism</topic><topic>Virus-Cell Interactions</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>You, Hongjuan</creatorcontrib><creatorcontrib>Lin, Yingying</creatorcontrib><creatorcontrib>Lin, Feng</creatorcontrib><creatorcontrib>Yang, Mingyue</creatorcontrib><creatorcontrib>Li, Jiahui</creatorcontrib><creatorcontrib>Zhang, Rongzhao</creatorcontrib><creatorcontrib>Huang, Zhiming</creatorcontrib><creatorcontrib>Shen, Qingtang</creatorcontrib><creatorcontrib>Tang, Renxian</creatorcontrib><creatorcontrib>Zheng, Chunfu</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>You, Hongjuan</au><au>Lin, Yingying</au><au>Lin, Feng</au><au>Yang, Mingyue</au><au>Li, Jiahui</au><au>Zhang, Rongzhao</au><au>Huang, Zhiming</au><au>Shen, Qingtang</au><au>Tang, Renxian</au><au>Zheng, Chunfu</au><au>Sandri-Goldin, Rozanne M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein</atitle><jtitle>Journal of virology</jtitle><addtitle>J Virol</addtitle><date>2020-02-14</date><risdate>2020</risdate><volume>94</volume><issue>5</issue><issn>0022-538X</issn><eissn>1098-5514</eissn><abstract>The cGAS/STING-mediated DNA-sensing signaling pathway is crucial for interferon (IFN) production and host antiviral responses. Herpes simplex virus I (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. Here, we demonstrate that the highly conserved β-catenin protein in the Wnt signaling pathway is an important factor to enhance the transcription of type I interferon (IFN-I) in the cGAS/STING signaling pathway, and the production of IFN-I mediated by β-catenin was antagonized by HSV-1 US3 protein via its kinase activity. Infection by US3-deficienct HSV-1 and its kinase-dead variants failed to downregulate IFN-I and IFN-stimulated gene (ISG) production induced by β-catenin. Consistent with this, absence of β-catenin enhanced the replication of US3-deficienct HSV-1, but not wild-type HSV-1. The underlying mechanism was the interaction of US3 with β-catenin and its hyperphosphorylation of β-catenin at Thr556 to block its nuclear translocation. For the first time, HSV-1 US3 has been shown to inhibit IFN-I production through hyperphosphorylation of β-catenin and to subvert host antiviral innate immunity.
Although increasing evidence has demonstrated that HSV-1 subverts host immune responses and establishes lifelong latent infection, the molecular mechanisms by which HSV-1 interrupts antiviral innate immunity, especially the cGAS/STING-mediated cellular DNA-sensing signaling pathway, have not been fully explored. Here, we show that β-catenin promotes cGAS/STING-mediated activation of the IFN pathway, which is important for cellular innate immune responses and intrinsic resistance to DNA virus infection. The protein kinase US3 antagonizes the production of IFN by targeting β-catenin via its kinase activity. The findings in this study reveal a novel mechanism for HSV-1 to evade host antiviral immunity and add new knowledge to help in understanding the interaction between the host and HSV-1 infection.</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>31801859</pmid><doi>10.1128/JVI.01847-19</doi><orcidid>https://orcid.org/0000-0002-8797-1322</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | A549 Cells Animals beta Catenin - genetics beta Catenin - metabolism Chlorocebus aethiops Cytokines Down-Regulation Gene Knockout Techniques HEK293 Cells Herpesvirus 1, Human - metabolism Humans Immunity, Innate Interferon Type I - metabolism Membrane Proteins - genetics Membrane Proteins - metabolism Nucleotidyltransferases - genetics Nucleotidyltransferases - metabolism Phosphorylation Protein Serine-Threonine Kinases - metabolism Signal Transduction Spotlight Vero Cells Viral Proteins - metabolism Virus-Cell Interactions |
title | β-Catenin Is Required for the cGAS/STING Signaling Pathway but Antagonized by the Herpes Simplex Virus 1 US3 Protein |
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