{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:12:34Z","timestamp":1792131154413,"version":"4.4.0"},"reference-count":60,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T00:00:00Z","timestamp":1634515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT153020"],"award-info":[{"award-number":["PJT153020"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The dengue virus (DENV) causes the most prevalent arthropod-borne viral disease worldwide. While its incidence is increasing in many countries, there is no approved antiviral therapy currently available. In infected cells, the DENV induces extensive morphological alterations of the endoplasmic reticulum (ER) to generate viral replication organelles (vRO), which include convoluted membranes (CM) and vesicle packets (VP) hosting viral RNA replication. The viral non-structural protein NS4B localizes to vROs and is absolutely required for viral replication through poorly defined mechanisms, which might involve cellular protein partners. Previous interactomic studies identified the ATPase valosin-containing protein (VCP) as a DENV NS4B-interacting host factor in infected cells. Using both pharmacological and dominant-negative inhibition approaches, we show, in this study, that VCP ATPase activity is required for efficient DENV replication. VCP associates with NS4B when expressed in the absence of other viral proteins while in infected cells, both proteins colocalize within large DENV-induced cytoplasmic structures previously demonstrated to be CMs. Consistently, VCP inhibition dramatically reduces the abundance of DENV CMs in infected cells. Most importantly, using a recently reported replication-independent plasmid-based vRO induction system, we show that de novo VP biogenesis is dependent on VCP ATPase activity. Overall, our data demonstrate that VCP ATPase activity is required for vRO morphogenesis and\/or stability. Considering that VCP was shown to be required for the replication of other flaviviruses, our results argue that VCP is a pan-flaviviral host dependency factor. Given that new generation VCP-targeting drugs are currently evaluated in clinical trials for cancer treatment, VCP may constitute an attractive broad-spectrum antiviral target in drug repurposing approaches.<\/jats:p>","DOI":"10.3390\/v13102092","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T22:07:04Z","timestamp":1634767624000},"page":"2092","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["The Biogenesis of Dengue Virus Replication Organelles Requires the ATPase Activity of Valosin-Containing Protein"],"prefix":"10.3390","volume":"13","author":[{"given":"Cl\u00e9ment","family":"Mazeaud","sequence":"first","affiliation":[{"name":"Centre Armand-Frappier Sant\u00e9 Biotechnologie, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3455-0882","authenticated-orcid":false,"given":"Ana\u00efs","family":"Anton","sequence":"additional","affiliation":[{"name":"Centre Armand-Frappier Sant\u00e9 Biotechnologie, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7445-2259","authenticated-orcid":false,"given":"Felix","family":"Pahmeier","sequence":"additional","affiliation":[{"name":"Center for Integrative Infectious Disease Research (CIID), Department of Infectious Diseases, Molecular Virology, Heidelberg University, D-69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0500-2625","authenticated-orcid":false,"given":"A\u00efssatou A\u00efcha","family":"Sow","sequence":"additional","affiliation":[{"name":"Centre Armand-Frappier Sant\u00e9 Biotechnologie, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berati","family":"Cerikan","sequence":"additional","affiliation":[{"name":"Center for Integrative Infectious Disease Research (CIID), Department of Infectious Diseases, Molecular Virology, Heidelberg University, D-69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3628-0465","authenticated-orcid":false,"given":"Wesley","family":"Freppel","sequence":"additional","affiliation":[{"name":"Centre Armand-Frappier Sant\u00e9 Biotechnologie, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1786-4211","authenticated-orcid":false,"given":"Mirko","family":"Cortese","sequence":"additional","affiliation":[{"name":"Center for Integrative Infectious Disease Research (CIID), Department of Infectious Diseases, Molecular Virology, Heidelberg University, D-69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5601-9307","authenticated-orcid":false,"given":"Ralf","family":"Bartenschlager","sequence":"additional","affiliation":[{"name":"Center for Integrative Infectious Disease Research (CIID), Department of Infectious Diseases, Molecular Virology, Heidelberg University, D-69120 Heidelberg, Germany"},{"name":"German Center for Infection Research (DZIF), Heidelberg Partner Site, D-69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7390-8250","authenticated-orcid":false,"given":"Laurent","family":"Chatel-Chaix","sequence":"additional","affiliation":[{"name":"Centre Armand-Frappier Sant\u00e9 Biotechnologie, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"},{"name":"Center of Excellence in Research on Orphan Diseases-Fondation Courtois, Montreal, QC H7V 1B7, Canada"},{"name":"R\u00e9seau Intersectoriel de Recherche en Sant\u00e9 de l\u2019Universit\u00e9 du Qu\u00e9bec, Qu\u00e9bec, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"Bhatt","year":"2013","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"120","DOI":"10.4103\/0974-2700.76835","article-title":"Dengue shock","volume":"4","author":"Rajapakse","year":"2011","journal-title":"J. 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