Valosin‐containing protein ATPase activity regulates the morphogenesis of Zika virus replication organelles and virus‐induced cell death
With no available therapies, infections with Zika virus (ZIKV) constitute a major public health concern as they can lead to congenital microcephaly. In order to generate an intracellular environment favourable to viral replication, ZIKV induces endomembrane remodelling and the morphogenesis of repli...
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creator | Anton, Anaïs Mazeaud, Clément Freppel, Wesley Gilbert, Claudia Tremblay, Nicolas Sow, Aïssatou Aïcha Roy, Marie Rodrigue‐Gervais, Ian Gaël Chatel‐Chaix, Laurent |
description | With no available therapies, infections with Zika virus (ZIKV) constitute a major public health concern as they can lead to congenital microcephaly. In order to generate an intracellular environment favourable to viral replication, ZIKV induces endomembrane remodelling and the morphogenesis of replication factories via enigmatic mechanisms. In this study, we identified the AAA+ type ATPase valosin‐containing protein (VCP) as a cellular interaction partner of ZIKV non‐structural protein 4B (NS4B). Importantly, its pharmacological inhibition as well as the expression of a VCP dominant‐negative mutant impaired ZIKV replication. In infected cells, VCP is relocalised to large ultrastructures containing both NS4B and NS3, which are reminiscent of dengue virus convoluted membranes. Moreover, short treatment with the VCP inhibitors NMS‐873 or CB‐5083 drastically decreased the abundance and size of ZIKV‐induced convoluted membranes. Furthermore, NMS‐873 treatment inhibited ZIKV‐induced mitochondria elongation previously reported to be physically and functionally linked to convoluted membranes in case of the closely related dengue virus. Finally, VCP inhibition resulted in enhanced apoptosis of ZIKV‐infected cells strongly suggesting that convoluted membranes limit virus‐induced cytopathic effects. Altogether, this study identifies VCP as a host factor required for ZIKV life cycle and more precisely, for the maintenance of viral replication factories. Our data further support a model in which convoluted membranes regulate ZIKV life cycle by impacting on mitochondrial functions and ZIKV‐induced death signals in order to create a cytoplasmic environment favourable to viral replication. |
doi_str_mv | 10.1111/cmi.13302 |
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In order to generate an intracellular environment favourable to viral replication, ZIKV induces endomembrane remodelling and the morphogenesis of replication factories via enigmatic mechanisms. In this study, we identified the AAA+ type ATPase valosin‐containing protein (VCP) as a cellular interaction partner of ZIKV non‐structural protein 4B (NS4B). Importantly, its pharmacological inhibition as well as the expression of a VCP dominant‐negative mutant impaired ZIKV replication. In infected cells, VCP is relocalised to large ultrastructures containing both NS4B and NS3, which are reminiscent of dengue virus convoluted membranes. Moreover, short treatment with the VCP inhibitors NMS‐873 or CB‐5083 drastically decreased the abundance and size of ZIKV‐induced convoluted membranes. Furthermore, NMS‐873 treatment inhibited ZIKV‐induced mitochondria elongation previously reported to be physically and functionally linked to convoluted membranes in case of the closely related dengue virus. Finally, VCP inhibition resulted in enhanced apoptosis of ZIKV‐infected cells strongly suggesting that convoluted membranes limit virus‐induced cytopathic effects. Altogether, this study identifies VCP as a host factor required for ZIKV life cycle and more precisely, for the maintenance of viral replication factories. Our data further support a model in which convoluted membranes regulate ZIKV life cycle by impacting on mitochondrial functions and ZIKV‐induced death signals in order to create a cytoplasmic environment favourable to viral replication.</description><identifier>ISSN: 1462-5814</identifier><identifier>EISSN: 1462-5822</identifier><identifier>DOI: 10.1111/cmi.13302</identifier><identifier>PMID: 33432690</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Inc</publisher><subject>Acetanilides ; Adenosine triphosphatase ; Adenosine Triphosphatases ; Animals ; Apoptosis ; Benzothiazoles ; Cell death ; Cell Line, Tumor ; Cellular structure ; Chlorocebus aethiops ; Dengue fever ; Elongation ; Factories ; Gene Expression Regulation ; HEK293 Cells ; Host Microbial Interactions ; Humans ; Indoles ; Life cycles ; Life Sciences ; Membranes ; Microencephaly ; Mitochondria ; Morphogenesis ; Organelles ; Proteins ; Public health ; Pyrimidines ; Replication ; Valosin Containing Protein ; Vector-borne diseases ; Vero Cells ; Viruses ; Zika Virus</subject><ispartof>Cellular microbiology, 2021-04, Vol.23 (4), p.e13302-n/a</ispartof><rights>2021 John Wiley & Sons Ltd</rights><rights>2021 John Wiley & Sons Ltd.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4222-830d46af5d22294c44beb5ac20ba2fccbe1c16b28ce2b63a9fdc7996b258a3083</citedby><cites>FETCH-LOGICAL-c4222-830d46af5d22294c44beb5ac20ba2fccbe1c16b28ce2b63a9fdc7996b258a3083</cites><orcidid>0000-0003-4246-7189 ; 0000-0003-3628-0465 ; 0000-0002-7390-8250 ; 0000-0003-1409-4442</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fcmi.13302$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fcmi.13302$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33432690$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03592017$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Anton, Anaïs</creatorcontrib><creatorcontrib>Mazeaud, Clément</creatorcontrib><creatorcontrib>Freppel, Wesley</creatorcontrib><creatorcontrib>Gilbert, Claudia</creatorcontrib><creatorcontrib>Tremblay, Nicolas</creatorcontrib><creatorcontrib>Sow, Aïssatou Aïcha</creatorcontrib><creatorcontrib>Roy, Marie</creatorcontrib><creatorcontrib>Rodrigue‐Gervais, Ian Gaël</creatorcontrib><creatorcontrib>Chatel‐Chaix, Laurent</creatorcontrib><title>Valosin‐containing protein ATPase activity regulates the morphogenesis of Zika virus replication organelles and virus‐induced cell death</title><title>Cellular microbiology</title><addtitle>Cell Microbiol</addtitle><description>With no available therapies, infections with Zika virus (ZIKV) constitute a major public health concern as they can lead to congenital microcephaly. In order to generate an intracellular environment favourable to viral replication, ZIKV induces endomembrane remodelling and the morphogenesis of replication factories via enigmatic mechanisms. In this study, we identified the AAA+ type ATPase valosin‐containing protein (VCP) as a cellular interaction partner of ZIKV non‐structural protein 4B (NS4B). Importantly, its pharmacological inhibition as well as the expression of a VCP dominant‐negative mutant impaired ZIKV replication. In infected cells, VCP is relocalised to large ultrastructures containing both NS4B and NS3, which are reminiscent of dengue virus convoluted membranes. Moreover, short treatment with the VCP inhibitors NMS‐873 or CB‐5083 drastically decreased the abundance and size of ZIKV‐induced convoluted membranes. Furthermore, NMS‐873 treatment inhibited ZIKV‐induced mitochondria elongation previously reported to be physically and functionally linked to convoluted membranes in case of the closely related dengue virus. Finally, VCP inhibition resulted in enhanced apoptosis of ZIKV‐infected cells strongly suggesting that convoluted membranes limit virus‐induced cytopathic effects. Altogether, this study identifies VCP as a host factor required for ZIKV life cycle and more precisely, for the maintenance of viral replication factories. Our data further support a model in which convoluted membranes regulate ZIKV life cycle by impacting on mitochondrial functions and ZIKV‐induced death signals in order to create a cytoplasmic environment favourable to viral replication.</description><subject>Acetanilides</subject><subject>Adenosine triphosphatase</subject><subject>Adenosine Triphosphatases</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Benzothiazoles</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cellular structure</subject><subject>Chlorocebus aethiops</subject><subject>Dengue fever</subject><subject>Elongation</subject><subject>Factories</subject><subject>Gene Expression Regulation</subject><subject>HEK293 Cells</subject><subject>Host Microbial Interactions</subject><subject>Humans</subject><subject>Indoles</subject><subject>Life cycles</subject><subject>Life Sciences</subject><subject>Membranes</subject><subject>Microencephaly</subject><subject>Mitochondria</subject><subject>Morphogenesis</subject><subject>Organelles</subject><subject>Proteins</subject><subject>Public health</subject><subject>Pyrimidines</subject><subject>Replication</subject><subject>Valosin Containing Protein</subject><subject>Vector-borne diseases</subject><subject>Vero Cells</subject><subject>Viruses</subject><subject>Zika Virus</subject><issn>1462-5814</issn><issn>1462-5822</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp1kc1uEzEQxy0EoqVw4AWQJS5wSOuv_fAxiqCtlIoeCgcu1qzXm7js2sH2BuXWB-DAM_IkON2SSkj4Ynv8m__M-I_Qa0pOaV5nerCnlHPCnqBjKko2K2rGnh7OVByhFzHeEkLLitLn6IhzwVkpyTH6-QV6H637ffdLe5fAOutWeBN8Mtbh-c01RINBJ7u1aYeDWY09JBNxWhs8-LBZ-5VxJtqIfYe_2m-AtzaMMZOb3mpI1jvswwqc6fucBq6dgFzPunbUpsU6P-HWQFq_RM866KN59bCfoM8fP9wsLmbLT-eXi_lypgVjbFZz0ooSuqLNNym0EI1pCtCMNMA6rRtDNS0bVmvDmpKD7FpdSZkjRQ2c1PwEvZ9019CrTbADhJ3yYNXFfKn2McILyQittjSz7yY2_8n30cSkBhv3LeeR_BgVE1XFyqIWMqNv_0Fv_RhcniRTUhZFWRP5WFwHH2Mw3aEDStTeTpXtVPd2ZvbNg-LYDKY9kH_9y8DZBPywvdn9X0ktri4nyT9hyq0U</recordid><startdate>202104</startdate><enddate>202104</enddate><creator>Anton, Anaïs</creator><creator>Mazeaud, Clément</creator><creator>Freppel, Wesley</creator><creator>Gilbert, Claudia</creator><creator>Tremblay, Nicolas</creator><creator>Sow, Aïssatou Aïcha</creator><creator>Roy, Marie</creator><creator>Rodrigue‐Gervais, Ian Gaël</creator><creator>Chatel‐Chaix, Laurent</creator><general>John Wiley & Sons, Inc</general><general>Hindawi Limited</general><general>Wiley</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7T7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0003-4246-7189</orcidid><orcidid>https://orcid.org/0000-0003-3628-0465</orcidid><orcidid>https://orcid.org/0000-0002-7390-8250</orcidid><orcidid>https://orcid.org/0000-0003-1409-4442</orcidid></search><sort><creationdate>202104</creationdate><title>Valosin‐containing protein ATPase activity regulates the morphogenesis of Zika virus replication organelles and virus‐induced cell death</title><author>Anton, Anaïs ; 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In order to generate an intracellular environment favourable to viral replication, ZIKV induces endomembrane remodelling and the morphogenesis of replication factories via enigmatic mechanisms. In this study, we identified the AAA+ type ATPase valosin‐containing protein (VCP) as a cellular interaction partner of ZIKV non‐structural protein 4B (NS4B). Importantly, its pharmacological inhibition as well as the expression of a VCP dominant‐negative mutant impaired ZIKV replication. In infected cells, VCP is relocalised to large ultrastructures containing both NS4B and NS3, which are reminiscent of dengue virus convoluted membranes. Moreover, short treatment with the VCP inhibitors NMS‐873 or CB‐5083 drastically decreased the abundance and size of ZIKV‐induced convoluted membranes. Furthermore, NMS‐873 treatment inhibited ZIKV‐induced mitochondria elongation previously reported to be physically and functionally linked to convoluted membranes in case of the closely related dengue virus. Finally, VCP inhibition resulted in enhanced apoptosis of ZIKV‐infected cells strongly suggesting that convoluted membranes limit virus‐induced cytopathic effects. Altogether, this study identifies VCP as a host factor required for ZIKV life cycle and more precisely, for the maintenance of viral replication factories. Our data further support a model in which convoluted membranes regulate ZIKV life cycle by impacting on mitochondrial functions and ZIKV‐induced death signals in order to create a cytoplasmic environment favourable to viral replication.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Inc</pub><pmid>33432690</pmid><doi>10.1111/cmi.13302</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0003-4246-7189</orcidid><orcidid>https://orcid.org/0000-0003-3628-0465</orcidid><orcidid>https://orcid.org/0000-0002-7390-8250</orcidid><orcidid>https://orcid.org/0000-0003-1409-4442</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Acetanilides Adenosine triphosphatase Adenosine Triphosphatases Animals Apoptosis Benzothiazoles Cell death Cell Line, Tumor Cellular structure Chlorocebus aethiops Dengue fever Elongation Factories Gene Expression Regulation HEK293 Cells Host Microbial Interactions Humans Indoles Life cycles Life Sciences Membranes Microencephaly Mitochondria Morphogenesis Organelles Proteins Public health Pyrimidines Replication Valosin Containing Protein Vector-borne diseases Vero Cells Viruses Zika Virus |
title | Valosin‐containing protein ATPase activity regulates the morphogenesis of Zika virus replication organelles and virus‐induced cell death |
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