Hepatitis C Virus Activates a Neuregulin-Driven Circuit to Modify Surface Expression of Growth Factor Receptors of the ErbB Family
Recently, the epidermal growth factor (EGF) receptor (EGFR), a member of the ErbB receptor family, and its down-stream signalling have been identified as co-factors for HCV entry and replication. Since EGFR also functions as a heterodimer with other ErbB receptor family members, the subject of the p...
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| Veröffentlicht in: | PloS one 2016-02, Vol.11 (2), p.e0148711 |
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| creator | Stindt, Sabine Cebula, Patricia Albrecht, Ute Keitel, Verena Schulte am Esch, Jan Knoefel, Wolfram T Bartenschlager, Ralf Häussinger, Dieter Bode, Johannes G |
| description | Recently, the epidermal growth factor (EGF) receptor (EGFR), a member of the ErbB receptor family, and its down-stream signalling have been identified as co-factors for HCV entry and replication. Since EGFR also functions as a heterodimer with other ErbB receptor family members, the subject of the present study was to investigate a possible viral interference with these cellular components. By using genotype 1b replicon cells as well as an infection-based system we found that while transcript and protein levels of EGFR and ErbB2 were up-regulated or unaffected, respectively, HCV induced a substantial reduction of ErbB3 and ErbB4 expression. Down-regulation of ErbB3 expression by HCV involves specificity protein (Sp)1-mediated induction of Neuregulin (NRG)1 expression as well as activation of Akt. Consistently, at transcript level disruption of ErbB3 expression by HCV can be prevented by knockdown of NRG1 or Sp1 expression, whereas reconstitution of ErbB3 protein levels requires inhibition of HCV-induced NRG1 expression and of Akt activity. Interestingly, the NRG1-mediated suppression of ErbB3 expression by HCV results in an enhanced expression of EGFR and ErbB2 on the cell surface, which can be mimicked by siRNA-mediated knockdown of ErbB3 expression. These data delineate a novel mechanism enabling HCV to sway the composition of the ErbB family members on the surface of its host cell by an NRG1-driven circuit and unravels a yet unknown cross-regulation between ErbB3 and the two other family members ErbB2 and EGFR. The shift of the receptor surface expression of the ErbB family towards enhanced expression of ErbB2 and EGFR triggered by HCV was found to promote viral RNA replication and infectivity. This suggests that HCV rearranges expression of ErbB family members to adapt the cellular environment to its requirements. |
| doi_str_mv | 10.1371/journal.pone.0148711 |
| format | Article |
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Since EGFR also functions as a heterodimer with other ErbB receptor family members, the subject of the present study was to investigate a possible viral interference with these cellular components. By using genotype 1b replicon cells as well as an infection-based system we found that while transcript and protein levels of EGFR and ErbB2 were up-regulated or unaffected, respectively, HCV induced a substantial reduction of ErbB3 and ErbB4 expression. Down-regulation of ErbB3 expression by HCV involves specificity protein (Sp)1-mediated induction of Neuregulin (NRG)1 expression as well as activation of Akt. Consistently, at transcript level disruption of ErbB3 expression by HCV can be prevented by knockdown of NRG1 or Sp1 expression, whereas reconstitution of ErbB3 protein levels requires inhibition of HCV-induced NRG1 expression and of Akt activity. Interestingly, the NRG1-mediated suppression of ErbB3 expression by HCV results in an enhanced expression of EGFR and ErbB2 on the cell surface, which can be mimicked by siRNA-mediated knockdown of ErbB3 expression. These data delineate a novel mechanism enabling HCV to sway the composition of the ErbB family members on the surface of its host cell by an NRG1-driven circuit and unravels a yet unknown cross-regulation between ErbB3 and the two other family members ErbB2 and EGFR. The shift of the receptor surface expression of the ErbB family towards enhanced expression of ErbB2 and EGFR triggered by HCV was found to promote viral RNA replication and infectivity. This suggests that HCV rearranges expression of ErbB family members to adapt the cellular environment to its requirements.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0148711</identifier><identifier>PMID: 26886748</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>AKT protein ; Apoptosis ; Binding sites ; Biology and life sciences ; Cell Differentiation - drug effects ; Cell division ; Cell Line, Tumor ; Cell Membrane - metabolism ; Cell surface ; Cellular proteins ; Cellular signal transduction ; Deoxyribonucleic acid ; Dimethyl Sulfoxide - pharmacology ; Disruption ; DNA ; Down-regulation ; Down-Regulation - drug effects ; Enzyme Activation - drug effects ; Epidermal growth factor ; Epidermal growth factor receptors ; Epiregulin - metabolism ; ErbB protein ; ErbB Receptors - metabolism ; ErbB-2 protein ; ErbB-3 protein ; Gastroenterology ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Genetic aspects ; Growth factor receptors ; Health aspects ; Hepacivirus - drug effects ; Hepacivirus - metabolism ; Hepacivirus - pathogenicity ; Hepatitis ; Hepatitis C ; Hepatitis C virus ; Hepatology ; Humans ; Infectious diseases ; Infectivity ; Kinases ; Ligands ; Medicine and health sciences ; Models, Biological ; Neuregulin ; Neuregulin 1 ; Neuregulin-1 - genetics ; Neuregulin-1 - metabolism ; Pediatrics ; Properties ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Receptor, Epidermal Growth Factor - metabolism ; Receptors ; Replication ; Research and analysis methods ; Ribonucleic acid ; RNA ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Rodents ; Signal transduction ; Signaling ; siRNA ; Sp1 protein ; Sp1 Transcription Factor - metabolism ; Transcription ; Up-Regulation - drug effects ; Virulence (Microbiology) ; Virus Replication - drug effects ; Viruses</subject><ispartof>PloS one, 2016-02, Vol.11 (2), p.e0148711</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Stindt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Stindt et al 2016 Stindt et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-8b22e1f0791edf16ea1f3215e1caccd114a9930afda30f2b25563d249a6259b73</citedby><cites>FETCH-LOGICAL-c692t-8b22e1f0791edf16ea1f3215e1caccd114a9930afda30f2b25563d249a6259b73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757098/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757098/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26886748$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Chai, Karl X</contributor><creatorcontrib>Stindt, Sabine</creatorcontrib><creatorcontrib>Cebula, Patricia</creatorcontrib><creatorcontrib>Albrecht, Ute</creatorcontrib><creatorcontrib>Keitel, Verena</creatorcontrib><creatorcontrib>Schulte am Esch, Jan</creatorcontrib><creatorcontrib>Knoefel, Wolfram T</creatorcontrib><creatorcontrib>Bartenschlager, Ralf</creatorcontrib><creatorcontrib>Häussinger, Dieter</creatorcontrib><creatorcontrib>Bode, Johannes G</creatorcontrib><title>Hepatitis C Virus Activates a Neuregulin-Driven Circuit to Modify Surface Expression of Growth Factor Receptors of the ErbB Family</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Recently, the epidermal growth factor (EGF) receptor (EGFR), a member of the ErbB receptor family, and its down-stream signalling have been identified as co-factors for HCV entry and replication. Since EGFR also functions as a heterodimer with other ErbB receptor family members, the subject of the present study was to investigate a possible viral interference with these cellular components. By using genotype 1b replicon cells as well as an infection-based system we found that while transcript and protein levels of EGFR and ErbB2 were up-regulated or unaffected, respectively, HCV induced a substantial reduction of ErbB3 and ErbB4 expression. Down-regulation of ErbB3 expression by HCV involves specificity protein (Sp)1-mediated induction of Neuregulin (NRG)1 expression as well as activation of Akt. Consistently, at transcript level disruption of ErbB3 expression by HCV can be prevented by knockdown of NRG1 or Sp1 expression, whereas reconstitution of ErbB3 protein levels requires inhibition of HCV-induced NRG1 expression and of Akt activity. Interestingly, the NRG1-mediated suppression of ErbB3 expression by HCV results in an enhanced expression of EGFR and ErbB2 on the cell surface, which can be mimicked by siRNA-mediated knockdown of ErbB3 expression. These data delineate a novel mechanism enabling HCV to sway the composition of the ErbB family members on the surface of its host cell by an NRG1-driven circuit and unravels a yet unknown cross-regulation between ErbB3 and the two other family members ErbB2 and EGFR. The shift of the receptor surface expression of the ErbB family towards enhanced expression of ErbB2 and EGFR triggered by HCV was found to promote viral RNA replication and infectivity. This suggests that HCV rearranges expression of ErbB family members to adapt the cellular environment to its requirements.</description><subject>AKT protein</subject><subject>Apoptosis</subject><subject>Binding sites</subject><subject>Biology and life sciences</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell division</subject><subject>Cell Line, Tumor</subject><subject>Cell Membrane - metabolism</subject><subject>Cell surface</subject><subject>Cellular proteins</subject><subject>Cellular signal transduction</subject><subject>Deoxyribonucleic acid</subject><subject>Dimethyl Sulfoxide - pharmacology</subject><subject>Disruption</subject><subject>DNA</subject><subject>Down-regulation</subject><subject>Down-Regulation - drug effects</subject><subject>Enzyme Activation - drug effects</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>Epiregulin - metabolism</subject><subject>ErbB protein</subject><subject>ErbB Receptors - metabolism</subject><subject>ErbB-2 protein</subject><subject>ErbB-3 protein</subject><subject>Gastroenterology</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genetic aspects</subject><subject>Growth factor receptors</subject><subject>Health aspects</subject><subject>Hepacivirus - drug effects</subject><subject>Hepacivirus - metabolism</subject><subject>Hepacivirus - pathogenicity</subject><subject>Hepatitis</subject><subject>Hepatitis C</subject><subject>Hepatitis C virus</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Infectivity</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Medicine and health sciences</subject><subject>Models, Biological</subject><subject>Neuregulin</subject><subject>Neuregulin 1</subject><subject>Neuregulin-1 - genetics</subject><subject>Neuregulin-1 - metabolism</subject><subject>Pediatrics</subject><subject>Properties</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>Receptors</subject><subject>Replication</subject><subject>Research and analysis methods</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>siRNA</subject><subject>Sp1 protein</subject><subject>Sp1 Transcription Factor - metabolism</subject><subject>Transcription</subject><subject>Up-Regulation - drug effects</subject><subject>Virulence (Microbiology)</subject><subject>Virus Replication - drug effects</subject><subject>Viruses</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1rFDEYhQdRbF39B6IBQfBi13zN102hrv2CaqHV3oZ3M292U2YnY5Kp3Vt_uVm7LbugILlIyPuck3A4Wfaa0QkTJft44wbfQTvpXYcTymRVMvYk22e14OOCU_F067yXvQjhhtJcVEXxPNvjRVUVpaz2s1-n2EO00QYyJdfWD4Ec6mhvIWIgQL7i4HE-tLYbf_b2FjsytV4PNpLoyBfXWLMiV4M3oJEc3fUeQ7CuI86QE-9-xgU5Bh2dJ5eosU-HsB7FRYL97FMaLm27epk9M9AGfLXZR9n346Nv09Px-cXJ2fTwfKyLmsdxNeMcmaFlzbAxrEBgRnCWI9OgdcOYhLoWFEwDgho-43leiIbLGgqe17NSjLK3975964LaxBcUK4u8ZkIk8Sg7uycaBzeq93YJfqUcWPXnwvm5Ah-tblFR5E1FgadAKwmNBINCYlPmRkiDBSSvg81rw2yJjcYuemh3THcnnV2oubtVssxLWlfJ4N3GwLsfA4b4jy9vqDmkX9nOuGSmlzZodSilyBmV1dpr8hcqrQaXVqcCGZvudwQfdgSJiXgX5zCEoM6uLv-fvbjeZd9vsQuENi6Ca4eYWhN2QXkPau9C8Ggek2NUrfv_kIZa919t-p9kb7ZTfxQ9FF78BgBwAWg</recordid><startdate>20160217</startdate><enddate>20160217</enddate><creator>Stindt, Sabine</creator><creator>Cebula, Patricia</creator><creator>Albrecht, Ute</creator><creator>Keitel, Verena</creator><creator>Schulte am Esch, Jan</creator><creator>Knoefel, Wolfram T</creator><creator>Bartenschlager, Ralf</creator><creator>Häussinger, Dieter</creator><creator>Bode, Johannes G</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20160217</creationdate><title>Hepatitis C Virus Activates a Neuregulin-Driven Circuit to Modify Surface Expression of Growth Factor Receptors of the ErbB Family</title><author>Stindt, Sabine ; Cebula, Patricia ; Albrecht, Ute ; Keitel, Verena ; Schulte am Esch, Jan ; Knoefel, Wolfram T ; Bartenschlager, Ralf ; Häussinger, Dieter ; Bode, Johannes G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-8b22e1f0791edf16ea1f3215e1caccd114a9930afda30f2b25563d249a6259b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>AKT protein</topic><topic>Apoptosis</topic><topic>Binding sites</topic><topic>Biology and life sciences</topic><topic>Cell Differentiation - 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metabolism</topic><topic>Hepacivirus - pathogenicity</topic><topic>Hepatitis</topic><topic>Hepatitis C</topic><topic>Hepatitis C virus</topic><topic>Hepatology</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>Infectivity</topic><topic>Kinases</topic><topic>Ligands</topic><topic>Medicine and health sciences</topic><topic>Models, Biological</topic><topic>Neuregulin</topic><topic>Neuregulin 1</topic><topic>Neuregulin-1 - genetics</topic><topic>Neuregulin-1 - metabolism</topic><topic>Pediatrics</topic><topic>Properties</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Receptor, Epidermal Growth Factor - metabolism</topic><topic>Receptors</topic><topic>Replication</topic><topic>Research and analysis methods</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>siRNA</topic><topic>Sp1 protein</topic><topic>Sp1 Transcription Factor - metabolism</topic><topic>Transcription</topic><topic>Up-Regulation - drug effects</topic><topic>Virulence (Microbiology)</topic><topic>Virus Replication - drug effects</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stindt, Sabine</creatorcontrib><creatorcontrib>Cebula, Patricia</creatorcontrib><creatorcontrib>Albrecht, Ute</creatorcontrib><creatorcontrib>Keitel, Verena</creatorcontrib><creatorcontrib>Schulte am Esch, Jan</creatorcontrib><creatorcontrib>Knoefel, Wolfram T</creatorcontrib><creatorcontrib>Bartenschlager, Ralf</creatorcontrib><creatorcontrib>Häussinger, Dieter</creatorcontrib><creatorcontrib>Bode, Johannes G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stindt, Sabine</au><au>Cebula, Patricia</au><au>Albrecht, Ute</au><au>Keitel, Verena</au><au>Schulte am Esch, Jan</au><au>Knoefel, Wolfram T</au><au>Bartenschlager, Ralf</au><au>Häussinger, Dieter</au><au>Bode, Johannes G</au><au>Chai, Karl X</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatitis C Virus Activates a Neuregulin-Driven Circuit to Modify Surface Expression of Growth Factor Receptors of the ErbB Family</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-02-17</date><risdate>2016</risdate><volume>11</volume><issue>2</issue><spage>e0148711</spage><pages>e0148711-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Recently, the epidermal growth factor (EGF) receptor (EGFR), a member of the ErbB receptor family, and its down-stream signalling have been identified as co-factors for HCV entry and replication. Since EGFR also functions as a heterodimer with other ErbB receptor family members, the subject of the present study was to investigate a possible viral interference with these cellular components. By using genotype 1b replicon cells as well as an infection-based system we found that while transcript and protein levels of EGFR and ErbB2 were up-regulated or unaffected, respectively, HCV induced a substantial reduction of ErbB3 and ErbB4 expression. Down-regulation of ErbB3 expression by HCV involves specificity protein (Sp)1-mediated induction of Neuregulin (NRG)1 expression as well as activation of Akt. Consistently, at transcript level disruption of ErbB3 expression by HCV can be prevented by knockdown of NRG1 or Sp1 expression, whereas reconstitution of ErbB3 protein levels requires inhibition of HCV-induced NRG1 expression and of Akt activity. Interestingly, the NRG1-mediated suppression of ErbB3 expression by HCV results in an enhanced expression of EGFR and ErbB2 on the cell surface, which can be mimicked by siRNA-mediated knockdown of ErbB3 expression. These data delineate a novel mechanism enabling HCV to sway the composition of the ErbB family members on the surface of its host cell by an NRG1-driven circuit and unravels a yet unknown cross-regulation between ErbB3 and the two other family members ErbB2 and EGFR. The shift of the receptor surface expression of the ErbB family towards enhanced expression of ErbB2 and EGFR triggered by HCV was found to promote viral RNA replication and infectivity. This suggests that HCV rearranges expression of ErbB family members to adapt the cellular environment to its requirements.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26886748</pmid><doi>10.1371/journal.pone.0148711</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-02, Vol.11 (2), p.e0148711 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1765913399 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | AKT protein Apoptosis Binding sites Biology and life sciences Cell Differentiation - drug effects Cell division Cell Line, Tumor Cell Membrane - metabolism Cell surface Cellular proteins Cellular signal transduction Deoxyribonucleic acid Dimethyl Sulfoxide - pharmacology Disruption DNA Down-regulation Down-Regulation - drug effects Enzyme Activation - drug effects Epidermal growth factor Epidermal growth factor receptors Epiregulin - metabolism ErbB protein ErbB Receptors - metabolism ErbB-2 protein ErbB-3 protein Gastroenterology Gene expression Gene Expression Regulation, Neoplastic - drug effects Genetic aspects Growth factor receptors Health aspects Hepacivirus - drug effects Hepacivirus - metabolism Hepacivirus - pathogenicity Hepatitis Hepatitis C Hepatitis C virus Hepatology Humans Infectious diseases Infectivity Kinases Ligands Medicine and health sciences Models, Biological Neuregulin Neuregulin 1 Neuregulin-1 - genetics Neuregulin-1 - metabolism Pediatrics Properties Proteins Proto-Oncogene Proteins c-akt - metabolism Receptor, Epidermal Growth Factor - metabolism Receptors Replication Research and analysis methods Ribonucleic acid RNA RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Signal transduction Signaling siRNA Sp1 protein Sp1 Transcription Factor - metabolism Transcription Up-Regulation - drug effects Virulence (Microbiology) Virus Replication - drug effects Viruses |
| title | Hepatitis C Virus Activates a Neuregulin-Driven Circuit to Modify Surface Expression of Growth Factor Receptors of the ErbB Family |
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