The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein
Previous studies have shown that both hepatitis A virus and hepatitis C virus inhibit innate immunity by cleaving the mitochondrial antiviral signaling (MAVS) protein, an essential component of the virus-activated signaling pathway that activates NF-kappaB and IFN regulatory factor-3 to induce the p...
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| Veröffentlicht in: | The Journal of immunology (1950) 2010-07, Vol.185 (2), p.1158-1168 |
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| container_title | The Journal of immunology (1950) |
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| creator | Wei, Congwen Ni, Caifei Song, Ting Liu, Yu Yang, XiaoLi Zheng, Zirui Jia, Yongxia Yuan, Yuan Guan, Kai Xu, Yang Cheng, Xiaozhong Zhang, Yanhong Yang, Xiao Wang, Youliang Wen, Chaoyang Wu, Qing Shi, Wei Zhong, Hui |
| description | Previous studies have shown that both hepatitis A virus and hepatitis C virus inhibit innate immunity by cleaving the mitochondrial antiviral signaling (MAVS) protein, an essential component of the virus-activated signaling pathway that activates NF-kappaB and IFN regulatory factor-3 to induce the production of type I IFN. For human hepatitis B virus (HBV), hepatitis B s-Ag, hepatitis B e-Ag, or HBV virions have been shown to suppress TLR-induced antiviral activity with reduced IFN-beta production and subsequent induction of IFN-stimulated genes. However, HBV-mediated suppression of the RIG-I-MDA5 pathway is unknown. In this study, we found that HBV suppressed poly(deoxyadenylate-thymidylate)-activated IFN-beta production in hepatocytes. Specifically, hepatitis B virus X (HBX) interacted with MAVS and promoted the degradation of MAVS through Lys(136) ubiquitin in MAVS protein, thus preventing the induction of IFN-beta. Further analysis of clinical samples revealed that MAVS protein was downregulated in hepatocellular carcinomas of HBV origin, which correlated with increased sensitivities of primary murine hepatocytes isolated from HBX knock-in transgenic mice upon vesicular stomatitis virus infections. By establishing a link between MAVS and HBX, this study suggests that HBV can target the RIG-I signaling by HBX-mediated MAVS downregulation, thereby attenuating the antiviral response of the innate immune system. |
| doi_str_mv | 10.4049/jimmunol.0903874 |
| format | Article |
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For human hepatitis B virus (HBV), hepatitis B s-Ag, hepatitis B e-Ag, or HBV virions have been shown to suppress TLR-induced antiviral activity with reduced IFN-beta production and subsequent induction of IFN-stimulated genes. However, HBV-mediated suppression of the RIG-I-MDA5 pathway is unknown. In this study, we found that HBV suppressed poly(deoxyadenylate-thymidylate)-activated IFN-beta production in hepatocytes. Specifically, hepatitis B virus X (HBX) interacted with MAVS and promoted the degradation of MAVS through Lys(136) ubiquitin in MAVS protein, thus preventing the induction of IFN-beta. Further analysis of clinical samples revealed that MAVS protein was downregulated in hepatocellular carcinomas of HBV origin, which correlated with increased sensitivities of primary murine hepatocytes isolated from HBX knock-in transgenic mice upon vesicular stomatitis virus infections. By establishing a link between MAVS and HBX, this study suggests that HBV can target the RIG-I signaling by HBX-mediated MAVS downregulation, thereby attenuating the antiviral response of the innate immune system.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.0903874</identifier><identifier>PMID: 20554965</identifier><language>eng</language><publisher>United States</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - immunology ; Adaptor Proteins, Signal Transducing - metabolism ; Animals ; Cell Line ; Chlorocebus aethiops ; DEAD Box Protein 58 ; DEAD-box RNA Helicases - genetics ; DEAD-box RNA Helicases - immunology ; DEAD-box RNA Helicases - metabolism ; Down-Regulation ; Hep G2 Cells ; Humans ; Immunity, Innate - immunology ; Immunoblotting ; Interferon-gamma - genetics ; Interferon-gamma - immunology ; Interferon-gamma - metabolism ; Kinetics ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - immunology ; Mitochondrial Proteins - metabolism ; Poly dA-dT - genetics ; Poly dA-dT - immunology ; Poly dA-dT - metabolism ; Protein Binding ; Receptors, Immunologic ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction - immunology ; Trans-Activators - genetics ; Trans-Activators - immunology ; Trans-Activators - metabolism ; Transfection ; Vero Cells ; Viral Regulatory and Accessory Proteins</subject><ispartof>The Journal of immunology (1950), 2010-07, Vol.185 (2), p.1158-1168</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-48bcdcde3d75754d2140888697132e248f4f397fcec843369f5854e483d5d2793</citedby><cites>FETCH-LOGICAL-c406t-48bcdcde3d75754d2140888697132e248f4f397fcec843369f5854e483d5d2793</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20554965$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wei, Congwen</creatorcontrib><creatorcontrib>Ni, Caifei</creatorcontrib><creatorcontrib>Song, Ting</creatorcontrib><creatorcontrib>Liu, Yu</creatorcontrib><creatorcontrib>Yang, XiaoLi</creatorcontrib><creatorcontrib>Zheng, Zirui</creatorcontrib><creatorcontrib>Jia, Yongxia</creatorcontrib><creatorcontrib>Yuan, Yuan</creatorcontrib><creatorcontrib>Guan, Kai</creatorcontrib><creatorcontrib>Xu, Yang</creatorcontrib><creatorcontrib>Cheng, Xiaozhong</creatorcontrib><creatorcontrib>Zhang, Yanhong</creatorcontrib><creatorcontrib>Yang, Xiao</creatorcontrib><creatorcontrib>Wang, Youliang</creatorcontrib><creatorcontrib>Wen, Chaoyang</creatorcontrib><creatorcontrib>Wu, Qing</creatorcontrib><creatorcontrib>Shi, Wei</creatorcontrib><creatorcontrib>Zhong, Hui</creatorcontrib><title>The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Previous studies have shown that both hepatitis A virus and hepatitis C virus inhibit innate immunity by cleaving the mitochondrial antiviral signaling (MAVS) protein, an essential component of the virus-activated signaling pathway that activates NF-kappaB and IFN regulatory factor-3 to induce the production of type I IFN. For human hepatitis B virus (HBV), hepatitis B s-Ag, hepatitis B e-Ag, or HBV virions have been shown to suppress TLR-induced antiviral activity with reduced IFN-beta production and subsequent induction of IFN-stimulated genes. However, HBV-mediated suppression of the RIG-I-MDA5 pathway is unknown. In this study, we found that HBV suppressed poly(deoxyadenylate-thymidylate)-activated IFN-beta production in hepatocytes. Specifically, hepatitis B virus X (HBX) interacted with MAVS and promoted the degradation of MAVS through Lys(136) ubiquitin in MAVS protein, thus preventing the induction of IFN-beta. Further analysis of clinical samples revealed that MAVS protein was downregulated in hepatocellular carcinomas of HBV origin, which correlated with increased sensitivities of primary murine hepatocytes isolated from HBX knock-in transgenic mice upon vesicular stomatitis virus infections. By establishing a link between MAVS and HBX, this study suggests that HBV can target the RIG-I signaling by HBX-mediated MAVS downregulation, thereby attenuating the antiviral response of the innate immune system.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - immunology</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Chlorocebus aethiops</subject><subject>DEAD Box Protein 58</subject><subject>DEAD-box RNA Helicases - genetics</subject><subject>DEAD-box RNA Helicases - immunology</subject><subject>DEAD-box RNA Helicases - metabolism</subject><subject>Down-Regulation</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Immunity, Innate - immunology</subject><subject>Immunoblotting</subject><subject>Interferon-gamma - genetics</subject><subject>Interferon-gamma - immunology</subject><subject>Interferon-gamma - metabolism</subject><subject>Kinetics</subject><subject>Mitochondrial Proteins - genetics</subject><subject>Mitochondrial Proteins - immunology</subject><subject>Mitochondrial Proteins - metabolism</subject><subject>Poly dA-dT - genetics</subject><subject>Poly dA-dT - immunology</subject><subject>Poly dA-dT - metabolism</subject><subject>Protein Binding</subject><subject>Receptors, Immunologic</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Signal Transduction - immunology</subject><subject>Trans-Activators - genetics</subject><subject>Trans-Activators - immunology</subject><subject>Trans-Activators - metabolism</subject><subject>Transfection</subject><subject>Vero Cells</subject><subject>Viral Regulatory and Accessory Proteins</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kDtPwzAUhS0EoqWwMyFvTCk38TMjIF5SJZYisUVp7LSuEifYDqj_HpemTPcO5ztH-hC6TmFOgeZ3W9O2g-2aOeRApKAnaJoyBgnnwE_RFCDLklRwMUEX3m8BgENGz9EkA8ZoztkUheVG443uy2CC8fgBfxs3ePyJe9cFbSxWxruhDx4ba8ug8d-iCTu82mHV_Vin10MTabvGrQldtemscqZscGmDiWXx82Zty2afGEsv0VldNl5fjXeGPp6flo-vyeL95e3xfpFUFHhIqFxVqlKaKMEEoypLKUgpeS5SkumMyprWJBd1pStJCeF5zSSjmkqimMpETmbo9tAbd78G7UPRGl_ppimt7gZfiAgRGmXFJBySleu8d7ouemfa0u2KFIq96uKouhhVR-RmLB9WrVb_wNEt-QUcHX6f</recordid><startdate>20100715</startdate><enddate>20100715</enddate><creator>Wei, Congwen</creator><creator>Ni, Caifei</creator><creator>Song, Ting</creator><creator>Liu, Yu</creator><creator>Yang, XiaoLi</creator><creator>Zheng, Zirui</creator><creator>Jia, Yongxia</creator><creator>Yuan, Yuan</creator><creator>Guan, Kai</creator><creator>Xu, Yang</creator><creator>Cheng, Xiaozhong</creator><creator>Zhang, Yanhong</creator><creator>Yang, Xiao</creator><creator>Wang, Youliang</creator><creator>Wen, Chaoyang</creator><creator>Wu, Qing</creator><creator>Shi, Wei</creator><creator>Zhong, Hui</creator><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></search><sort><creationdate>20100715</creationdate><title>The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein</title><author>Wei, Congwen ; Ni, Caifei ; Song, Ting ; Liu, Yu ; Yang, XiaoLi ; Zheng, Zirui ; Jia, Yongxia ; Yuan, Yuan ; Guan, Kai ; Xu, Yang ; Cheng, Xiaozhong ; Zhang, Yanhong ; Yang, Xiao ; Wang, Youliang ; Wen, Chaoyang ; Wu, Qing ; Shi, Wei ; Zhong, Hui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-48bcdcde3d75754d2140888697132e248f4f397fcec843369f5854e483d5d2793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - immunology</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Chlorocebus aethiops</topic><topic>DEAD Box Protein 58</topic><topic>DEAD-box RNA Helicases - genetics</topic><topic>DEAD-box RNA Helicases - immunology</topic><topic>DEAD-box RNA Helicases - metabolism</topic><topic>Down-Regulation</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Immunity, Innate - immunology</topic><topic>Immunoblotting</topic><topic>Interferon-gamma - genetics</topic><topic>Interferon-gamma - immunology</topic><topic>Interferon-gamma - metabolism</topic><topic>Kinetics</topic><topic>Mitochondrial Proteins - genetics</topic><topic>Mitochondrial Proteins - immunology</topic><topic>Mitochondrial Proteins - metabolism</topic><topic>Poly dA-dT - genetics</topic><topic>Poly dA-dT - immunology</topic><topic>Poly dA-dT - metabolism</topic><topic>Protein Binding</topic><topic>Receptors, Immunologic</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Signal Transduction - immunology</topic><topic>Trans-Activators - genetics</topic><topic>Trans-Activators - immunology</topic><topic>Trans-Activators - metabolism</topic><topic>Transfection</topic><topic>Vero Cells</topic><topic>Viral Regulatory and Accessory Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wei, Congwen</creatorcontrib><creatorcontrib>Ni, Caifei</creatorcontrib><creatorcontrib>Song, Ting</creatorcontrib><creatorcontrib>Liu, Yu</creatorcontrib><creatorcontrib>Yang, XiaoLi</creatorcontrib><creatorcontrib>Zheng, Zirui</creatorcontrib><creatorcontrib>Jia, Yongxia</creatorcontrib><creatorcontrib>Yuan, Yuan</creatorcontrib><creatorcontrib>Guan, Kai</creatorcontrib><creatorcontrib>Xu, Yang</creatorcontrib><creatorcontrib>Cheng, Xiaozhong</creatorcontrib><creatorcontrib>Zhang, Yanhong</creatorcontrib><creatorcontrib>Yang, Xiao</creatorcontrib><creatorcontrib>Wang, Youliang</creatorcontrib><creatorcontrib>Wen, Chaoyang</creatorcontrib><creatorcontrib>Wu, Qing</creatorcontrib><creatorcontrib>Shi, Wei</creatorcontrib><creatorcontrib>Zhong, Hui</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><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wei, Congwen</au><au>Ni, Caifei</au><au>Song, Ting</au><au>Liu, Yu</au><au>Yang, XiaoLi</au><au>Zheng, Zirui</au><au>Jia, Yongxia</au><au>Yuan, Yuan</au><au>Guan, Kai</au><au>Xu, Yang</au><au>Cheng, Xiaozhong</au><au>Zhang, Yanhong</au><au>Yang, Xiao</au><au>Wang, Youliang</au><au>Wen, Chaoyang</au><au>Wu, Qing</au><au>Shi, Wei</au><au>Zhong, Hui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2010-07-15</date><risdate>2010</risdate><volume>185</volume><issue>2</issue><spage>1158</spage><epage>1168</epage><pages>1158-1168</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><abstract>Previous studies have shown that both hepatitis A virus and hepatitis C virus inhibit innate immunity by cleaving the mitochondrial antiviral signaling (MAVS) protein, an essential component of the virus-activated signaling pathway that activates NF-kappaB and IFN regulatory factor-3 to induce the production of type I IFN. For human hepatitis B virus (HBV), hepatitis B s-Ag, hepatitis B e-Ag, or HBV virions have been shown to suppress TLR-induced antiviral activity with reduced IFN-beta production and subsequent induction of IFN-stimulated genes. However, HBV-mediated suppression of the RIG-I-MDA5 pathway is unknown. In this study, we found that HBV suppressed poly(deoxyadenylate-thymidylate)-activated IFN-beta production in hepatocytes. Specifically, hepatitis B virus X (HBX) interacted with MAVS and promoted the degradation of MAVS through Lys(136) ubiquitin in MAVS protein, thus preventing the induction of IFN-beta. Further analysis of clinical samples revealed that MAVS protein was downregulated in hepatocellular carcinomas of HBV origin, which correlated with increased sensitivities of primary murine hepatocytes isolated from HBX knock-in transgenic mice upon vesicular stomatitis virus infections. By establishing a link between MAVS and HBX, this study suggests that HBV can target the RIG-I signaling by HBX-mediated MAVS downregulation, thereby attenuating the antiviral response of the innate immune system.</abstract><cop>United States</cop><pmid>20554965</pmid><doi>10.4049/jimmunol.0903874</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - immunology Adaptor Proteins, Signal Transducing - metabolism Animals Cell Line Chlorocebus aethiops DEAD Box Protein 58 DEAD-box RNA Helicases - genetics DEAD-box RNA Helicases - immunology DEAD-box RNA Helicases - metabolism Down-Regulation Hep G2 Cells Humans Immunity, Innate - immunology Immunoblotting Interferon-gamma - genetics Interferon-gamma - immunology Interferon-gamma - metabolism Kinetics Mitochondrial Proteins - genetics Mitochondrial Proteins - immunology Mitochondrial Proteins - metabolism Poly dA-dT - genetics Poly dA-dT - immunology Poly dA-dT - metabolism Protein Binding Receptors, Immunologic Reverse Transcriptase Polymerase Chain Reaction Signal Transduction - immunology Trans-Activators - genetics Trans-Activators - immunology Trans-Activators - metabolism Transfection Vero Cells Viral Regulatory and Accessory Proteins |
| title | The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein |
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