Enhanced alpha1 microglobulin secretion from Hepatitis E virus ORF3-expressing human hepatoma cells is mediated by the tumor susceptibility gene 101
Viruses are known to exploit the host cell machinery for their benefit during different stages of their life cycle within the infected host. One of the major challenges for a virus during the early stages of infection is to escape recognition by the host immune system. Viruses have adopted many nove...
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Veröffentlicht in: | The Journal of biological chemistry 2006-03, Vol.281 (12), p.8135-8142 |
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description | Viruses are known to exploit the host cell machinery for their benefit during different stages of their life cycle within the infected host. One of the major challenges for a virus during the early stages of infection is to escape recognition by the host immune system. Viruses have adopted many novel strategies to evade the host immune response or to create an immune suppressed environment. An earlier study in our laboratory has demonstrated that the ORF3 protein of the hepatitis E virus expedites the secretion of alpha1 microglobulin, an immunosuppressant molecule. Based on this observation, we proposed that enhanced secretion of alpha1 microglobulin may help maintain an immunosuppressed milieu around the infected hepatocyte (Tyagi, S., Surjit, M., Roy, A. K., Jameel, S., and Lal, S. K. (2004) J. Biol. Chem. 279, 29308-29319). In the present study, we discovered that the ability of the ORF3 protein to expedite alpha1 microglobulin secretion is attributed to the PSAP motif present at the C terminus of the former. The ORF3 protein was able to associate with the tumor susceptibility gene 101 (TSG101) through the PSAP motif. Further, a PSAP motif-mutated ORF3 protein was unable to associate with TSG101 and also lost its ability to enhance the secretion of alpha1 microglobulin. In addition, the ORF3 protein was found to associate simultaneously with TSG101 and alpha1 microglobulin because all three of them were co-precipitated as a ternary complex. Finally, a dominant negative mutant of the VPS4 protein was shown to block the enhanced alpha1 microglobulin secretion in ORF3-expressing hepatocytes. These results suggest a mechanism by which the ORF3 protein exploits the endosomal sorting machinery to enhance the secretion of an immunosuppressant molecule (alpha1 microglobulin) from the cultured hepatocytes. |
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One of the major challenges for a virus during the early stages of infection is to escape recognition by the host immune system. Viruses have adopted many novel strategies to evade the host immune response or to create an immune suppressed environment. An earlier study in our laboratory has demonstrated that the ORF3 protein of the hepatitis E virus expedites the secretion of alpha1 microglobulin, an immunosuppressant molecule. Based on this observation, we proposed that enhanced secretion of alpha1 microglobulin may help maintain an immunosuppressed milieu around the infected hepatocyte (Tyagi, S., Surjit, M., Roy, A. K., Jameel, S., and Lal, S. K. (2004) J. Biol. Chem. 279, 29308-29319). In the present study, we discovered that the ability of the ORF3 protein to expedite alpha1 microglobulin secretion is attributed to the PSAP motif present at the C terminus of the former. The ORF3 protein was able to associate with the tumor susceptibility gene 101 (TSG101) through the PSAP motif. Further, a PSAP motif-mutated ORF3 protein was unable to associate with TSG101 and also lost its ability to enhance the secretion of alpha1 microglobulin. In addition, the ORF3 protein was found to associate simultaneously with TSG101 and alpha1 microglobulin because all three of them were co-precipitated as a ternary complex. Finally, a dominant negative mutant of the VPS4 protein was shown to block the enhanced alpha1 microglobulin secretion in ORF3-expressing hepatocytes. These results suggest a mechanism by which the ORF3 protein exploits the endosomal sorting machinery to enhance the secretion of an immunosuppressant molecule (alpha1 microglobulin) from the cultured hepatocytes.</description><identifier>ISSN: 0021-9258</identifier><identifier>PMID: 16407257</identifier><language>eng</language><publisher>United States</publisher><subject>Alpha-Globulins - metabolism ; Amino Acid Motifs ; Amino Acid Sequence ; Carcinoma, Hepatocellular - metabolism ; Cell Line, Tumor ; DNA-Binding Proteins - metabolism ; Endosomal Sorting Complexes Required for Transport ; Endosomes - metabolism ; Hepatitis E virus - genetics ; Hepatocytes - metabolism ; Humans ; Immunoblotting ; Immunoprecipitation ; Immunosuppressive Agents - metabolism ; Microscopy, Fluorescence ; Molecular Sequence Data ; Mutation ; Open Reading Frames ; Plasmids - metabolism ; Protein Binding ; Sequence Homology, Amino Acid ; Transcription Factors - metabolism ; Transfection ; Two-Hybrid System Techniques ; Viral Proteins - metabolism ; Viral Proteins - physiology</subject><ispartof>The Journal of biological chemistry, 2006-03, Vol.281 (12), p.8135-8142</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16407257$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Surjit, Milan</creatorcontrib><creatorcontrib>Oberoi, Ruchi</creatorcontrib><creatorcontrib>Kumar, Ravinder</creatorcontrib><creatorcontrib>Lal, Sunil K</creatorcontrib><title>Enhanced alpha1 microglobulin secretion from Hepatitis E virus ORF3-expressing human hepatoma cells is mediated by the tumor susceptibility gene 101</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Viruses are known to exploit the host cell machinery for their benefit during different stages of their life cycle within the infected host. One of the major challenges for a virus during the early stages of infection is to escape recognition by the host immune system. Viruses have adopted many novel strategies to evade the host immune response or to create an immune suppressed environment. An earlier study in our laboratory has demonstrated that the ORF3 protein of the hepatitis E virus expedites the secretion of alpha1 microglobulin, an immunosuppressant molecule. Based on this observation, we proposed that enhanced secretion of alpha1 microglobulin may help maintain an immunosuppressed milieu around the infected hepatocyte (Tyagi, S., Surjit, M., Roy, A. K., Jameel, S., and Lal, S. K. (2004) J. Biol. Chem. 279, 29308-29319). In the present study, we discovered that the ability of the ORF3 protein to expedite alpha1 microglobulin secretion is attributed to the PSAP motif present at the C terminus of the former. The ORF3 protein was able to associate with the tumor susceptibility gene 101 (TSG101) through the PSAP motif. Further, a PSAP motif-mutated ORF3 protein was unable to associate with TSG101 and also lost its ability to enhance the secretion of alpha1 microglobulin. In addition, the ORF3 protein was found to associate simultaneously with TSG101 and alpha1 microglobulin because all three of them were co-precipitated as a ternary complex. Finally, a dominant negative mutant of the VPS4 protein was shown to block the enhanced alpha1 microglobulin secretion in ORF3-expressing hepatocytes. These results suggest a mechanism by which the ORF3 protein exploits the endosomal sorting machinery to enhance the secretion of an immunosuppressant molecule (alpha1 microglobulin) from the cultured hepatocytes.</description><subject>Alpha-Globulins - metabolism</subject><subject>Amino Acid Motifs</subject><subject>Amino Acid Sequence</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Cell Line, Tumor</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Endosomal Sorting Complexes Required for Transport</subject><subject>Endosomes - metabolism</subject><subject>Hepatitis E virus - genetics</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Immunoprecipitation</subject><subject>Immunosuppressive Agents - metabolism</subject><subject>Microscopy, Fluorescence</subject><subject>Molecular Sequence Data</subject><subject>Mutation</subject><subject>Open Reading Frames</subject><subject>Plasmids - metabolism</subject><subject>Protein Binding</subject><subject>Sequence Homology, Amino Acid</subject><subject>Transcription Factors - metabolism</subject><subject>Transfection</subject><subject>Two-Hybrid System Techniques</subject><subject>Viral Proteins - metabolism</subject><subject>Viral Proteins - physiology</subject><issn>0021-9258</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kMFOwzAQRHMA0VL4BbQnbpFsx3WSI6pailSpEuo92jjbxiiOg-0g-h98MKkoe5nLm9mdvUnmjAmelmJZzJL7ED7YNLLkd8mMK8lyscznyc-6b7HX1AB2Q4scrNHenTpXj53pIZD2FI3r4eidhS0NGE00AdbwZfwYYP--yVL6HjyFYPoTtKPFHtoL5yyCpq4LMPGWGoNxWlOfIbYEcbTOQxiDpiGa2nQmnuFEPQFn_CG5PWIX6PGqi-SwWR9W23S3f31bvezSYSnzlI4NSuRCiDIvCplJrIupkxJS5-xYsEJwzbXKUCHnhWKMkDWl0qoWiLKU2SJ5_osdvPscKcTKmnC5GHtyY6hUnk-uspzApys41lORavDGoj9X_2_MfgFM1273</recordid><startdate>20060324</startdate><enddate>20060324</enddate><creator>Surjit, Milan</creator><creator>Oberoi, Ruchi</creator><creator>Kumar, Ravinder</creator><creator>Lal, Sunil K</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20060324</creationdate><title>Enhanced alpha1 microglobulin secretion from Hepatitis E virus ORF3-expressing human hepatoma cells is mediated by the tumor susceptibility gene 101</title><author>Surjit, Milan ; Oberoi, Ruchi ; Kumar, Ravinder ; Lal, Sunil K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p547-efda4a12229788434ab8257624c70f80821c1c63a6a118600ea0d96c6b2aa4943</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Alpha-Globulins - metabolism</topic><topic>Amino Acid Motifs</topic><topic>Amino Acid Sequence</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Cell Line, Tumor</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Endosomal Sorting Complexes Required for Transport</topic><topic>Endosomes - metabolism</topic><topic>Hepatitis E virus - genetics</topic><topic>Hepatocytes - metabolism</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Immunoprecipitation</topic><topic>Immunosuppressive Agents - metabolism</topic><topic>Microscopy, Fluorescence</topic><topic>Molecular Sequence Data</topic><topic>Mutation</topic><topic>Open Reading Frames</topic><topic>Plasmids - metabolism</topic><topic>Protein Binding</topic><topic>Sequence Homology, Amino Acid</topic><topic>Transcription Factors - metabolism</topic><topic>Transfection</topic><topic>Two-Hybrid System Techniques</topic><topic>Viral Proteins - metabolism</topic><topic>Viral Proteins - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Surjit, Milan</creatorcontrib><creatorcontrib>Oberoi, Ruchi</creatorcontrib><creatorcontrib>Kumar, Ravinder</creatorcontrib><creatorcontrib>Lal, Sunil K</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Surjit, Milan</au><au>Oberoi, Ruchi</au><au>Kumar, Ravinder</au><au>Lal, Sunil K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enhanced alpha1 microglobulin secretion from Hepatitis E virus ORF3-expressing human hepatoma cells is mediated by the tumor susceptibility gene 101</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2006-03-24</date><risdate>2006</risdate><volume>281</volume><issue>12</issue><spage>8135</spage><epage>8142</epage><pages>8135-8142</pages><issn>0021-9258</issn><abstract>Viruses are known to exploit the host cell machinery for their benefit during different stages of their life cycle within the infected host. One of the major challenges for a virus during the early stages of infection is to escape recognition by the host immune system. Viruses have adopted many novel strategies to evade the host immune response or to create an immune suppressed environment. An earlier study in our laboratory has demonstrated that the ORF3 protein of the hepatitis E virus expedites the secretion of alpha1 microglobulin, an immunosuppressant molecule. Based on this observation, we proposed that enhanced secretion of alpha1 microglobulin may help maintain an immunosuppressed milieu around the infected hepatocyte (Tyagi, S., Surjit, M., Roy, A. K., Jameel, S., and Lal, S. K. (2004) J. Biol. Chem. 279, 29308-29319). In the present study, we discovered that the ability of the ORF3 protein to expedite alpha1 microglobulin secretion is attributed to the PSAP motif present at the C terminus of the former. The ORF3 protein was able to associate with the tumor susceptibility gene 101 (TSG101) through the PSAP motif. Further, a PSAP motif-mutated ORF3 protein was unable to associate with TSG101 and also lost its ability to enhance the secretion of alpha1 microglobulin. In addition, the ORF3 protein was found to associate simultaneously with TSG101 and alpha1 microglobulin because all three of them were co-precipitated as a ternary complex. Finally, a dominant negative mutant of the VPS4 protein was shown to block the enhanced alpha1 microglobulin secretion in ORF3-expressing hepatocytes. These results suggest a mechanism by which the ORF3 protein exploits the endosomal sorting machinery to enhance the secretion of an immunosuppressant molecule (alpha1 microglobulin) from the cultured hepatocytes.</abstract><cop>United States</cop><pmid>16407257</pmid><tpages>8</tpages></addata></record> |
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subjects | Alpha-Globulins - metabolism Amino Acid Motifs Amino Acid Sequence Carcinoma, Hepatocellular - metabolism Cell Line, Tumor DNA-Binding Proteins - metabolism Endosomal Sorting Complexes Required for Transport Endosomes - metabolism Hepatitis E virus - genetics Hepatocytes - metabolism Humans Immunoblotting Immunoprecipitation Immunosuppressive Agents - metabolism Microscopy, Fluorescence Molecular Sequence Data Mutation Open Reading Frames Plasmids - metabolism Protein Binding Sequence Homology, Amino Acid Transcription Factors - metabolism Transfection Two-Hybrid System Techniques Viral Proteins - metabolism Viral Proteins - physiology |
title | Enhanced alpha1 microglobulin secretion from Hepatitis E virus ORF3-expressing human hepatoma cells is mediated by the tumor susceptibility gene 101 |
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