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We identify the host metalloprotease ADAM17 as a facilitator of SARS\u2010CoV\u20102 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID\u201019 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARS\u2010CoV\u20102 spike protein (S)\n                    <jats:italic>in vitro<\/jats:italic>\n                    , indicating that ADAM10 and ADAM17 contribute to the priming of S, an essential step for viral entry and cell fusion. ADAM protease\u2010targeted inhibitors severely impair lung cell infection by the SARS\u2010CoV\u20102 variants of concern alpha, beta, delta, and omicron and also reduce SARS\u2010CoV\u20102 infection of primary human lung cells in a TMPRSS2 protease\u2010independent manner. Our study establishes ADAM10 and ADAM17 as host cell factors for viral entry and syncytia formation and defines both proteases as potential targets for antiviral drug development.\n                  <\/jats:p>","DOI":"10.15252\/embr.202154305","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T02:40:29Z","timestamp":1652064029000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":131,"title":["ADAM10 and ADAM17 promote SARS\u2010CoV\u20102 cell entry and spike protein\u2010mediated lung cell fusion"],"prefix":"10.1038","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7089-3487","authenticated-orcid":false,"given":"Georg","family":"Jocher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7710-4789","authenticated-orcid":false,"given":"Vincent","family":"Grass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah K","family":"Tschirner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7879-5566","authenticated-orcid":false,"given":"Lydia","family":"Riepler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0305-3373","authenticated-orcid":false,"given":"Stephan","family":"Breimann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tu\u011fberk","family":"Kaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madlen","family":"Oelsner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3684-6388","authenticated-orcid":false,"given":"M Sabri","family":"Hamad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura I","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5053-3137","authenticated-orcid":false,"given":"Carl P","family":"Blobel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3203-8084","authenticated-orcid":false,"given":"Carsten B","family":"Schmidt\u2010Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozgun","family":"Gokce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanze A","family":"Jakwerth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1616-0810","authenticated-orcid":false,"given":"Jakob","family":"Trimpert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5210-7905","authenticated-orcid":false,"given":"Janine","family":"Kimpel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0166-1367","authenticated-orcid":false,"given":"Andreas","family":"Pichlmair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2211-2575","authenticated-orcid":false,"given":"Stefan F","family":"Lichtenthaler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,8]]},"reference":[{"key":"BFEMBR202154305_CR1","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1038\/s41586-020-2312-y","volume":"583","author":"L Bao","year":"2020","unstructured":"Bao L, Deng W, Huang B, Gao H, Liu J, Ren L, Wei Q, Yu P, Xu Y, Qi F et al (2020) The pathogenicity of SARS\u2010CoV\u20102 in hACE2 transgenic mice. 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Dr. Blobel holds a patent on a method of identifying agents for combination with inhibitors of iRhoms. Dr. Blobel and the Hospital for Special Surgery have identified iRhom2 inhibitors and have co\u2010founded the start\u2010up company SciRhom in Munich to commercialize these inhibitors.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}],"article-number":"EMBR202154305"}}