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Here, we report that the disintegrin and matrix metalloproteinase 10 (ADAM10) associates with CD81, SR-BI, and EGFR and acts as HCV host factor. Pharmacological inhibition, siRNA-mediated silencing and genetic ablation of ADAM10 reduced HCV infection. ADAM10 was dispensable for HCV replication but supported HCV entry and cell-to-cell spread. Substrates of the ADAM10 sheddase including epidermal growth factor (EGF) and E-cadherin, which activate EGFR family members, rescued HCV infection of ADAM10 knockout cells. ADAM10 did not influence infection with other enveloped RNA viruses such as alphaviruses and a common cold coronavirus. Collectively, our study reveals a critical role for the sheddase ADAM10 as a HCV host factor, contributing to EGFR family member transactivation and as a consequence to HCV uptake.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011759","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T18:27:23Z","timestamp":1700072843000},"page":"e1011759","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["The matrix metalloproteinase ADAM10 supports hepatitis C virus entry and cell-to-cell spread via its sheddase activity"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0640-3041","authenticated-orcid":true,"given":"Bel\u00e9n","family":"Carriqu\u00ed-Madro\u00f1al","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Sheldon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Duven","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cora","family":"Stegmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karsten","family":"Cirksena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuel","family":"Wyler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Zapatero-Belinch\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian W. R.","family":"Vondran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1326-5038","authenticated-orcid":true,"given":"Gisa","family":"Gerold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,11,15]]},"reference":[{"issue":"4902","key":"ppat.1011759.ref001","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1126\/science.2523562","article-title":"Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome","volume":"244","author":"QL Choo","year":"1989","journal-title":"Science"},{"issue":"5","key":"ppat.1011759.ref002","doi-asserted-by":"crossref","first-page":"691","DOI":"10.7326\/0003-4819-77-5-691","article-title":"Posttransfusion hepatitis after exclusion of commercial and hepatitis-B antigen-positive donors","volume":"77","author":"HJ Alter","year":"1972","journal-title":"Ann Intern Med"},{"issue":"8062","key":"ppat.1011759.ref003","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S0140-6736(78)90131-9","article-title":"Transmissible agent in non-A, non-B hepatitis.","volume":"1","author":"HJ Alter","year":"1978","journal-title":"Lancet"},{"issue":"1","key":"ppat.1011759.ref004","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1055\/s-0030-1247128","article-title":"Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis","volume":"30","author":"M. Sherman","year":"2010","journal-title":"Semin Liver Dis"},{"issue":"9916","key":"ppat.1011759.ref005","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/S0140-6736(13)62121-2","article-title":"Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial.","volume":"383","author":"E Lawitz","year":"2014","journal-title":"Lancet"},{"issue":"1","key":"ppat.1011759.ref006","doi-asserted-by":"crossref","first-page":"e86413","DOI":"10.1371\/journal.pone.0086413","article-title":"HCV genotypes, characterization of mutations conferring drug resistance to protease inhibitors, and risk factors among blood donors in S\u00e3o Paulo, Brazil.","volume":"9","author":"AS Nishiya","year":"2014","journal-title":"PLoS 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Scarselli","year":"2002","journal-title":"EMBO J"},{"issue":"5390","key":"ppat.1011759.ref010","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1126\/science.282.5390.938","article-title":"Binding of hepatitis C virus to CD81","volume":"282","author":"P Pileri","year":"1998","journal-title":"Science"},{"issue":"19","key":"ppat.1011759.ref011","doi-asserted-by":"crossref","first-page":"7270","DOI":"10.1073\/pnas.0402253101","article-title":"CD81 is an entry coreceptor for hepatitis C virus","volume":"101","author":"EG Cormier","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"issue":"3","key":"ppat.1011759.ref012","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1128\/JVI.78.3.1448-1455.2004","article-title":"CD81 is required for hepatitis C virus glycoprotein-mediated viral infection","volume":"78","author":"J Zhang","year":"2004","journal-title":"J 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Sci"},{"issue":"5","key":"ppat.1011759.ref031","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1083\/jcb.200307137","article-title":"Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands","volume":"164","author":"U Sahin","year":"2004","journal-title":"J Cell Biol"},{"issue":"26","key":"ppat.1011759.ref032","doi-asserted-by":"crossref","first-page":"9182","DOI":"10.1073\/pnas.0500918102","article-title":"ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation","volume":"102","author":"T Maretzky","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"issue":"6","key":"ppat.1011759.ref033","doi-asserted-by":"crossref","first-page":"e54305","DOI":"10.15252\/embr.202154305","article-title":"ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion","volume":"23","author":"G Jocher","year":"2022","journal-title":"EMBO Rep"},{"key":"ppat.1011759.ref034","article-title":"ADAM17-dependent signaling is required for oncogenic human papillomavirus entry platform assembly.","author":"S Mikuli\u010di\u0107","year":"2019","journal-title":"eLife"},{"issue":"24","key":"ppat.1011759.ref035","doi-asserted-by":"crossref","first-page":"13001","DOI":"10.1128\/JVI.76.24.13001-13014.2002","article-title":"Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication","volume":"76","author":"KJ Blight","year":"2002","journal-title":"J Virol"},{"issue":"7","key":"ppat.1011759.ref036","doi-asserted-by":"crossref","first-page":"e101386","DOI":"10.1371\/journal.pone.0101386","article-title":"Explanted diseased livers\u2014a possible source of metabolic competent primary human hepatocytes.","volume":"9","author":"M Kleine","year":"2014","journal-title":"PLoS 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Sanjana","year":"2014","journal-title":"Nat Methods."},{"issue":"Web Server issue","key":"ppat.1011759.ref055","doi-asserted-by":"crossref","first-page":"W401","DOI":"10.1093\/nar\/gku410","article-title":"CHOPCHOP: a CRISPR\/Cas9 and TALEN web tool for genome editing","volume":"42","author":"TG Montague","year":"2014","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"ppat.1011759.ref056","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/nmeth.1318","article-title":"Enzymatic assembly of DNA molecules up to several hundred kilobases","volume":"6","author":"DG Gibson","year":"2009","journal-title":"Nat Methods"},{"issue":"7768","key":"ppat.1011759.ref057","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41586-019-1373-2","article-title":"A human liver cell atlas reveals heterogeneity and epithelial progenitors","volume":"572","author":"N Aizarani","year":"2019","journal-title":"Nature"},{"issue":"10","key":"ppat.1011759.ref058","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00245-21","article-title":"Initial HCV infection of adult hepatocytes triggers a temporally structured transcriptional program containing diverse pro- and anti-viral elements","volume":"95","author":"B Tegtmeyer","year":"2021","journal-title":"J Virol"},{"issue":"1","key":"ppat.1011759.ref059","doi-asserted-by":"crossref","first-page":"11414","DOI":"10.1038\/s41598-021-90716-3","article-title":"ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis","volume":"11","author":"O Zbodakova","year":"2021","journal-title":"Sci Rep"},{"issue":"2","key":"ppat.1011759.ref060","doi-asserted-by":"crossref","first-page":"161","DOI":"10.2174\/1386207053258488","article-title":"Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol 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