The KSHV Immediate-Early Transcription Factor RTA Encodes Ubiquitin E3 Ligase Activity that Targets IRF7 for Proteosome-Mediated Degradation
Many viruses encode proteins that counteract the development of the interferon (IFN)-mediated antiviral state. Here, we report that interferon regulatory factor 7 (IRF7), a key mediator of type I IFN induction, is targeted for degradation by binding to the RTA immediate-early nuclear transcription f...
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| Veröffentlicht in: | Immunity (Cambridge, Mass.) Mass.), 2005, Vol.22 (1), p.59-70 |
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| creator | Yu, Yanxing Wang, Shizhen Emily Hayward, Gary S. |
| description | Many viruses encode proteins that counteract the development of the interferon (IFN)-mediated antiviral state. Here, we report that interferon regulatory factor 7 (IRF7), a key mediator of type I IFN induction, is targeted for degradation by binding to the RTA immediate-early nuclear transcription factor encoded by Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8). Cotransfection with RTA blocked IRF7-mediated IFNα and IFNβ mRNA production and promoted the ubiquitination and degradation of IRF7 protein in a proteasome-dependent fashion. Addition of RTA also promoted polyubiquitination of IRF7 in an in vitro cell free assay, demonstrating that RTA itself acts as a ubiquitin E3 ligase. RTA also autoregulated its own polyubiquitination and stability, and both activities were abolished by point mutations in a Cys plus His-rich N-terminal domain. Therefore, manipulation of the stability and function of IRF7 by the KSHV RTA transcription factor provides an unexpected regulatory strategy for circumventing the innate immune defence system. |
| doi_str_mv | 10.1016/j.immuni.2004.11.011 |
| format | Article |
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Here, we report that interferon regulatory factor 7 (IRF7), a key mediator of type I IFN induction, is targeted for degradation by binding to the RTA immediate-early nuclear transcription factor encoded by Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8). Cotransfection with RTA blocked IRF7-mediated IFNα and IFNβ mRNA production and promoted the ubiquitination and degradation of IRF7 protein in a proteasome-dependent fashion. Addition of RTA also promoted polyubiquitination of IRF7 in an in vitro cell free assay, demonstrating that RTA itself acts as a ubiquitin E3 ligase. RTA also autoregulated its own polyubiquitination and stability, and both activities were abolished by point mutations in a Cys plus His-rich N-terminal domain. Therefore, manipulation of the stability and function of IRF7 by the KSHV RTA transcription factor provides an unexpected regulatory strategy for circumventing the innate immune defence system.</description><identifier>ISSN: 1074-7613</identifier><identifier>EISSN: 1097-4180</identifier><identifier>DOI: 10.1016/j.immuni.2004.11.011</identifier><identifier>PMID: 15664159</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Deoxyribonucleic acid ; DNA ; DNA-Binding Proteins - metabolism ; Enzymes ; Gene Expression Regulation, Viral ; Genes ; Genetic Vectors ; HeLa Cells ; Herpesvirus 8, Human - genetics ; Humans ; Interferon Regulatory Factor-7 ; Kaposi's sarcoma-associated herpesvirus ; Mutagenesis, Site-Directed ; Phosphorylation ; Plasmids ; Promoter Regions, Genetic ; Protein Binding ; Proteins ; Substrate Specificity ; Trans-Activators - genetics ; Trans-Activators - metabolism ; Transcription factors ; Transfection ; Tumor Cells, Cultured ; Ubiquitin-Protein Ligases - metabolism ; Virus Activation</subject><ispartof>Immunity (Cambridge, Mass.), 2005, Vol.22 (1), p.59-70</ispartof><rights>2005 Elsevier Inc.</rights><rights>Copyright Elsevier Limited Jan 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c465t-f3da926784431a36e3b7a09b7fea6fd9a4a223434262daeed2a47892a1af35a93</citedby><cites>FETCH-LOGICAL-c465t-f3da926784431a36e3b7a09b7fea6fd9a4a223434262daeed2a47892a1af35a93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.immuni.2004.11.011$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,4024,27923,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15664159$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, Yanxing</creatorcontrib><creatorcontrib>Wang, Shizhen Emily</creatorcontrib><creatorcontrib>Hayward, Gary S.</creatorcontrib><title>The KSHV Immediate-Early Transcription Factor RTA Encodes Ubiquitin E3 Ligase Activity that Targets IRF7 for Proteosome-Mediated Degradation</title><title>Immunity (Cambridge, Mass.)</title><addtitle>Immunity</addtitle><description>Many viruses encode proteins that counteract the development of the interferon (IFN)-mediated antiviral state. Here, we report that interferon regulatory factor 7 (IRF7), a key mediator of type I IFN induction, is targeted for degradation by binding to the RTA immediate-early nuclear transcription factor encoded by Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8). Cotransfection with RTA blocked IRF7-mediated IFNα and IFNβ mRNA production and promoted the ubiquitination and degradation of IRF7 protein in a proteasome-dependent fashion. Addition of RTA also promoted polyubiquitination of IRF7 in an in vitro cell free assay, demonstrating that RTA itself acts as a ubiquitin E3 ligase. RTA also autoregulated its own polyubiquitination and stability, and both activities were abolished by point mutations in a Cys plus His-rich N-terminal domain. Therefore, manipulation of the stability and function of IRF7 by the KSHV RTA transcription factor provides an unexpected regulatory strategy for circumventing the innate immune defence system.</description><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Enzymes</subject><subject>Gene Expression Regulation, Viral</subject><subject>Genes</subject><subject>Genetic Vectors</subject><subject>HeLa Cells</subject><subject>Herpesvirus 8, Human - genetics</subject><subject>Humans</subject><subject>Interferon Regulatory Factor-7</subject><subject>Kaposi's sarcoma-associated herpesvirus</subject><subject>Mutagenesis, Site-Directed</subject><subject>Phosphorylation</subject><subject>Plasmids</subject><subject>Promoter Regions, Genetic</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Substrate Specificity</subject><subject>Trans-Activators - genetics</subject><subject>Trans-Activators - metabolism</subject><subject>Transcription factors</subject><subject>Transfection</subject><subject>Tumor Cells, Cultured</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><subject>Virus Activation</subject><issn>1074-7613</issn><issn>1097-4180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFr20AQhUVpadK0_6CUhUJvUne0q13rUjCpnZi6tKRKr8tYGjlrLK2zuwr4P_RHV0aGQg49zRy-N294L0neA8-Ag_q8y2zXDb3Ncs5lBpBxgBfJJfBSpxJm_OVp1zLVCsRF8iaEHecgi5K_Ti6gUEpCUV4mf6oHYt9-3f5mq66jxmKkdIF-f2SVxz7U3h6idT1bYh2dZ3fVnC362jUU2P3GPg422p4tBFvbLQZi8zraJxuPLD5gZBX6LcXAVndLzdpR_tO7SC64jtLvk1nDvtLWY4Mnl7fJqxb3gd6d51Vyv1xU17fp-sfN6nq-Tmupipi2osEyV3ompQAUisRGIy83uiVUbVOixDwXUshc5Q0SNTlKPStzBGxFgaW4Sj5Ndw_ePQ4UoulsqGm_x57cEAxoLeVM6BH8-AzcucH3428GCi5zwZWGkZITVXsXgqfWHLzt0B8NcHPqyuzM1JU5dWUAzNjVKPtwPj5sxuj_ic7ljMCXCaAxiydL3oTaUl-PyXmqo2mc_b_DX7Jdpxs</recordid><startdate>2005</startdate><enddate>2005</enddate><creator>Yu, Yanxing</creator><creator>Wang, Shizhen Emily</creator><creator>Hayward, Gary S.</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>2005</creationdate><title>The KSHV Immediate-Early Transcription Factor RTA Encodes Ubiquitin E3 Ligase Activity that Targets IRF7 for Proteosome-Mediated Degradation</title><author>Yu, Yanxing ; Wang, Shizhen Emily ; Hayward, Gary S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c465t-f3da926784431a36e3b7a09b7fea6fd9a4a223434262daeed2a47892a1af35a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Enzymes</topic><topic>Gene Expression Regulation, Viral</topic><topic>Genes</topic><topic>Genetic Vectors</topic><topic>HeLa Cells</topic><topic>Herpesvirus 8, Human - genetics</topic><topic>Humans</topic><topic>Interferon Regulatory Factor-7</topic><topic>Kaposi's sarcoma-associated herpesvirus</topic><topic>Mutagenesis, Site-Directed</topic><topic>Phosphorylation</topic><topic>Plasmids</topic><topic>Promoter Regions, Genetic</topic><topic>Protein Binding</topic><topic>Proteins</topic><topic>Substrate Specificity</topic><topic>Trans-Activators - genetics</topic><topic>Trans-Activators - metabolism</topic><topic>Transcription factors</topic><topic>Transfection</topic><topic>Tumor Cells, Cultured</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><topic>Virus Activation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yu, Yanxing</creatorcontrib><creatorcontrib>Wang, Shizhen Emily</creatorcontrib><creatorcontrib>Hayward, Gary S.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Immunity (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, Yanxing</au><au>Wang, Shizhen Emily</au><au>Hayward, Gary S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The KSHV Immediate-Early Transcription Factor RTA Encodes Ubiquitin E3 Ligase Activity that Targets IRF7 for Proteosome-Mediated Degradation</atitle><jtitle>Immunity (Cambridge, Mass.)</jtitle><addtitle>Immunity</addtitle><date>2005</date><risdate>2005</risdate><volume>22</volume><issue>1</issue><spage>59</spage><epage>70</epage><pages>59-70</pages><issn>1074-7613</issn><eissn>1097-4180</eissn><abstract>Many viruses encode proteins that counteract the development of the interferon (IFN)-mediated antiviral state. Here, we report that interferon regulatory factor 7 (IRF7), a key mediator of type I IFN induction, is targeted for degradation by binding to the RTA immediate-early nuclear transcription factor encoded by Kaposi's sarcoma-associated herpesvirus (KSHV or HHV8). Cotransfection with RTA blocked IRF7-mediated IFNα and IFNβ mRNA production and promoted the ubiquitination and degradation of IRF7 protein in a proteasome-dependent fashion. Addition of RTA also promoted polyubiquitination of IRF7 in an in vitro cell free assay, demonstrating that RTA itself acts as a ubiquitin E3 ligase. RTA also autoregulated its own polyubiquitination and stability, and both activities were abolished by point mutations in a Cys plus His-rich N-terminal domain. 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| source | MEDLINE; Cell Press Free Archives; Access via ScienceDirect (Elsevier); EZB-FREE-00999 freely available EZB journals |
| subjects | Deoxyribonucleic acid DNA DNA-Binding Proteins - metabolism Enzymes Gene Expression Regulation, Viral Genes Genetic Vectors HeLa Cells Herpesvirus 8, Human - genetics Humans Interferon Regulatory Factor-7 Kaposi's sarcoma-associated herpesvirus Mutagenesis, Site-Directed Phosphorylation Plasmids Promoter Regions, Genetic Protein Binding Proteins Substrate Specificity Trans-Activators - genetics Trans-Activators - metabolism Transcription factors Transfection Tumor Cells, Cultured Ubiquitin-Protein Ligases - metabolism Virus Activation |
| title | The KSHV Immediate-Early Transcription Factor RTA Encodes Ubiquitin E3 Ligase Activity that Targets IRF7 for Proteosome-Mediated Degradation |
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