Hepatitis E Virus ORF2 Protein Activates the Pro-Apoptotic Gene CHOP and Anti-Apoptotic Heat Shock Proteins
Identifieur interne : 000A10 ( Pmc/Curation ); précédent : 000A09; suivant : 000A11Hepatitis E Virus ORF2 Protein Activates the Pro-Apoptotic Gene CHOP and Anti-Apoptotic Heat Shock Proteins
Auteurs : Lijo John ; Saijo Thomas ; Ottmar Herchenröder ; Brigitte M. Pützer ; Stephan SchaeferSource :
- PLoS ONE [ 1932-6203 ] ; 2011.
Abstract
Hepatitis E virus (HEV) is a non-enveloped plus-strand RNA virus that causes acute hepatitis. The capsid protein open reading frame 2 (ORF2) is known to induce endoplasmic reticulum stress in ORF2 expressing cells.
In this study we found that HEV ORF2 activates the expression of the pro-apoptotic gene C/EBP homologous protein (CHOP). ORF2 stimulates the CHOP promoter mainly through AARE (amino acid response elements) and to a minor extent the ERSE (endoplasmic reticulum stress response elements). Activating transcription factor 4 (ATF4) protein binds and activates the AARE regulatory sites of the CHOP promoter. ORF2 expression also leads to increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) that in turn initiates the translation of ATF4 mRNA. The pro-apoptotic gene CHOP is an important trigger to initiate endoplasmic reticulum stress induced apoptosis. However, the activation of CHOP by ORF2 in this study did not induce apoptosis, nor did BCL2-associated X protein (Bax) translocate to mitochondria. Microarray analysis revealed an ORF2 specific increased expression of chaperones Hsp72, Hsp70B', and co-chaperone Hsp40. Co-immunoprecipitation (Co-IP) and
These data provide new insight into simultaneously occurring counter-acting effects of HEV ORF2 that may be part of a strategy to prevent host suicide before completion of the viral replication cycle.
Url:
DOI: 10.1371/journal.pone.0025378
PubMed: 21966512
PubMed Central: 3179511
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Hepatitis E Virus ORF2 Protein Activates the Pro-Apoptotic Gene CHOP and Anti-Apoptotic Heat Shock Proteins</title><author><name sortKey="John, Lijo" sort="John, Lijo" uniqKey="John L" first="Lijo" last="John">Lijo John</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Thomas, Saijo" sort="Thomas, Saijo" uniqKey="Thomas S" first="Saijo" last="Thomas">Saijo Thomas</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Herchenroder, Ottmar" sort="Herchenroder, Ottmar" uniqKey="Herchenroder O" first="Ottmar" last="Herchenröder">Ottmar Herchenröder</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Putzer, Brigitte M" sort="Putzer, Brigitte M" uniqKey="Putzer B" first="Brigitte M." last="Pützer">Brigitte M. Pützer</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Schaefer, Stephan" sort="Schaefer, Stephan" uniqKey="Schaefer S" first="Stephan" last="Schaefer">Stephan Schaefer</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21966512</idno><idno type="pmc">3179511</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179511</idno><idno type="RBID">PMC:3179511</idno><idno type="doi">10.1371/journal.pone.0025378</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000A10</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A10</idno><idno type="wicri:Area/Pmc/Curation">000A10</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A10</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Hepatitis E Virus ORF2 Protein Activates the Pro-Apoptotic Gene CHOP and Anti-Apoptotic Heat Shock Proteins</title><author><name sortKey="John, Lijo" sort="John, Lijo" uniqKey="John L" first="Lijo" last="John">Lijo John</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Thomas, Saijo" sort="Thomas, Saijo" uniqKey="Thomas S" first="Saijo" last="Thomas">Saijo Thomas</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Herchenroder, Ottmar" sort="Herchenroder, Ottmar" uniqKey="Herchenroder O" first="Ottmar" last="Herchenröder">Ottmar Herchenröder</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Putzer, Brigitte M" sort="Putzer, Brigitte M" uniqKey="Putzer B" first="Brigitte M." last="Pützer">Brigitte M. Pützer</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Schaefer, Stephan" sort="Schaefer, Stephan" uniqKey="Schaefer S" first="Stephan" last="Schaefer">Stephan Schaefer</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Hepatitis E virus (HEV) is a non-enveloped plus-strand RNA virus that causes acute hepatitis. The capsid protein open reading frame 2 (ORF2) is known to induce endoplasmic reticulum stress in ORF2 expressing cells.</p></sec><sec><title>Methodology/Principal Findings</title><p>In this study we found that HEV ORF2 activates the expression of the pro-apoptotic gene C/EBP homologous protein (CHOP). ORF2 stimulates the CHOP promoter mainly through AARE (amino acid response elements) and to a minor extent the ERSE (endoplasmic reticulum stress response elements). Activating transcription factor 4 (ATF4) protein binds and activates the AARE regulatory sites of the CHOP promoter. ORF2 expression also leads to increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) that in turn initiates the translation of ATF4 mRNA. The pro-apoptotic gene CHOP is an important trigger to initiate endoplasmic reticulum stress induced apoptosis. However, the activation of CHOP by ORF2 in this study did not induce apoptosis, nor did BCL2-associated X protein (Bax) translocate to mitochondria. Microarray analysis revealed an ORF2 specific increased expression of chaperones Hsp72, Hsp70B', and co-chaperone Hsp40. Co-immunoprecipitation (Co-IP) and <italic>in silico</italic> molecular docking analysis suggests that HEV ORF2 interacts with Hsp72. In addition, Hsp72 shows nuclear accumulation in ORF2 expressing cells.</p></sec><sec><title>Conclusions/Significance</title><p>These data provide new insight into simultaneously occurring counter-acting effects of HEV ORF2 that may be part of a strategy to prevent host suicide before completion of the viral replication cycle.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Chandra, V" uniqKey="Chandra V">V Chandra</name></author><author><name sortKey="Taneja, S" uniqKey="Taneja S">S Taneja</name></author><author><name sortKey="Kalia, M" uniqKey="Kalia M">M Kalia</name></author><author><name sortKey="Jameel, S" uniqKey="Jameel S">S Jameel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ahmad, I" uniqKey="Ahmad I">I Ahmad</name></author><author><name sortKey="Holla, Rp" uniqKey="Holla R">RP Holla</name></author><author><name sortKey="Jameel, S" uniqKey="Jameel S">S 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21966512</article-id><article-id pub-id-type="pmc">3179511</article-id><article-id pub-id-type="publisher-id">PONE-D-11-09398</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0025378</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Computational Biology</subject><subj-group><subject>Microarrays</subject></subj-group></subj-group><subj-group><subject>Genetics</subject><subj-group><subject>Gene Expression</subject></subj-group></subj-group><subj-group><subject>Microbiology</subject><subj-group><subject>Virology</subject><subj-group><subject>Virulence Factors and Mechanisms</subject></subj-group></subj-group></subj-group><subj-group><subject>Molecular Cell Biology</subject><subj-group><subject>Gene Expression</subject></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Hepatitis E Virus ORF2 Protein Activates the Pro-Apoptotic Gene CHOP and Anti-Apoptotic Heat Shock Proteins</article-title><alt-title alt-title-type="running-head">Regulation of ER Stress Response by HEV ORF2</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>John</surname><given-names>Lijo</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>Saijo</given-names></name><xref ref-type="aff" rid="aff1"></xref><xref ref-type="author-notes" rid="fn1"><sup>¤</sup></xref></contrib><contrib contrib-type="author"><name><surname>Herchenröder</surname><given-names>Ottmar</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Pützer</surname><given-names>Brigitte M.</given-names></name><xref ref-type="aff" rid="aff1"></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schaefer</surname><given-names>Stephan</given-names></name><xref ref-type="aff" rid="aff1"></xref></contrib></contrib-group><aff id="aff1"><addr-line>Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, University of Rostock Medical School, Rostock, Germany</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Jin</surname><given-names>Dong-Yan</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">University of Hong Kong, Hong Kong</aff><author-notes><corresp id="cor1">* E-mail: <email>brigitte.puetzer@med.uni-rostock.de</email></corresp><fn fn-type="con"><p>Conceived and designed the experiments: LJ ST BMP. Performed the experiments: LJ ST. Analyzed the data: LJ ST OH BMP SS. Wrote the paper: LJ SS OH BMP.</p></fn><fn id="fn1" fn-type="current-aff"><label>¤</label><p>Current address: EMBL Grenoble, High Throughput Protein Lab, Grenoble, France</p></fn></author-notes><pub-date pub-type="collection"><year>2011</year></pub-date><pub-date pub-type="epub"><day>23</day><month>9</month><year>2011</year></pub-date><volume>6</volume><issue>9</issue><elocation-id>e25378</elocation-id><history><date date-type="received"><day>24</day><month>5</month><year>2011</year></date><date date-type="accepted"><day>2</day><month>9</month><year>2011</year></date></history><permissions><copyright-statement>John et al.</copyright-statement><copyright-year>2011</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><abstract><sec><title>Background</title><p>Hepatitis E virus (HEV) is a non-enveloped plus-strand RNA virus that causes acute hepatitis. The capsid protein open reading frame 2 (ORF2) is known to induce endoplasmic reticulum stress in ORF2 expressing cells.</p></sec><sec><title>Methodology/Principal Findings</title><p>In this study we found that HEV ORF2 activates the expression of the pro-apoptotic gene C/EBP homologous protein (CHOP). ORF2 stimulates the CHOP promoter mainly through AARE (amino acid response elements) and to a minor extent the ERSE (endoplasmic reticulum stress response elements). Activating transcription factor 4 (ATF4) protein binds and activates the AARE regulatory sites of the CHOP promoter. ORF2 expression also leads to increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) that in turn initiates the translation of ATF4 mRNA. The pro-apoptotic gene CHOP is an important trigger to initiate endoplasmic reticulum stress induced apoptosis. However, the activation of CHOP by ORF2 in this study did not induce apoptosis, nor did BCL2-associated X protein (Bax) translocate to mitochondria. Microarray analysis revealed an ORF2 specific increased expression of chaperones Hsp72, Hsp70B', and co-chaperone Hsp40. Co-immunoprecipitation (Co-IP) and <italic>in silico</italic> molecular docking analysis suggests that HEV ORF2 interacts with Hsp72. In addition, Hsp72 shows nuclear accumulation in ORF2 expressing cells.</p></sec><sec><title>Conclusions/Significance</title><p>These data provide new insight into simultaneously occurring counter-acting effects of HEV ORF2 that may be part of a strategy to prevent host suicide before completion of the viral replication cycle.</p></sec></abstract><counts><page-count count="10"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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