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Although TMPRSS2 is a well-characterized type II transmembrane serine protease (TTSP), the role of other TTSPs on the replication of SARS-CoV-2 remains to be elucidated. Here, we have screened 12 TTSPs using human angiotensin-converting enzyme 2-expressing HEK293T (293T-ACE2) cells and Vero E6 cells and demonstrated that exogenous expression of TMPRSS11D and TMPRSS13 enhanced cellular uptake and subsequent replication of SARS-CoV-2. In addition, SARS-CoV-1 and SARS-CoV-2 share the same TTSPs in the viral entry process. Our study demonstrates the impact of host TTSPs on infection of SARS-CoV-2, which may have implications for cell and tissue tropism, for pathogenicity, and potentially for vaccine development.<\/jats:p>","DOI":"10.3390\/v13030384","type":"journal-article","created":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T20:43:32Z","timestamp":1614545012000},"page":"384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":97,"title":["TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein"],"prefix":"10.3390","volume":"13","author":[{"given":"Mai","family":"Kishimoto","sequence":"first","affiliation":[{"name":"Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, N20 W10, Kita-ku, Sapporo 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Uemura","sequence":"additional","affiliation":[{"name":"Drug Discovery and Disease Research Laboratory, Shionogi &amp; Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan"},{"name":"Division of Anti-Virus Drug Research, Research Center for Zoonosis Control, Hokkaido University, N20 W10, Kita-ku, Sapporo 001-0020, Japan"},{"name":"Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo 060-0812, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8847-0071","authenticated-orcid":false,"given":"Takao","family":"Sanaki","sequence":"additional","affiliation":[{"name":"Drug Discovery and Disease Research Laboratory, Shionogi &amp; Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan"},{"name":"Division of Anti-Virus Drug Research, Research Center for Zoonosis Control, Hokkaido University, N20 W10, Kita-ku, Sapporo 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Sato","sequence":"additional","affiliation":[{"name":"Drug Discovery and Disease Research Laboratory, Shionogi &amp; Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan"},{"name":"Division of Anti-Virus Drug Research, Research Center for Zoonosis Control, Hokkaido University, N20 W10, Kita-ku, Sapporo 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William W.","family":"Hall","sequence":"additional","affiliation":[{"name":"National Virus Reference Laboratory, School of Medicine, University College Dublin, DO4V1W8 Dublin, Ireland"},{"name":"Centre for Research in Infectious Diseases, School of Medicine, University College Dublin, DO4V1W8 Dublin, Ireland"},{"name":"International Collaboration Unit, Research Center for Zoonosis Control, Hokkaido University, N20 W10, Kita-ku, Sapporo 001-0020, Japan"},{"name":"Global Virus Network, 725 West Lombard St, Room S413, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Kariwa","sequence":"additional","affiliation":[{"name":"Laboratory of Public Health, Faculty of Veterinary Medicine, Hokkaido University, N18 W9, Kita-ku, Sapporo 060-0818, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9910-3912","authenticated-orcid":false,"given":"Yasuko","family":"Orba","sequence":"additional","affiliation":[{"name":"Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, N20 W10, Kita-ku, Sapporo 001-0020, Japan"},{"name":"International Collaboration Unit, Research Center for Zoonosis Control, Hokkaido University, N20 W10, Kita-ku, Sapporo 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Sawa","sequence":"additional","affiliation":[{"name":"Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, N20 W10, Kita-ku, Sapporo 001-0020, Japan"},{"name":"International Collaboration Unit, Research Center for Zoonosis Control, Hokkaido University, N20 W10, Kita-ku, Sapporo 001-0020, Japan"},{"name":"Global Virus Network, 725 West Lombard St, Room S413, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1607-2175","authenticated-orcid":false,"given":"Michihito","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, N20 W10, Kita-ku, Sapporo 001-0020, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","article-title":"A New Coronavirus Associated with Human Respiratory Disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/j.it.2020.10.004","article-title":"Mechanisms of SARS-CoV-2 Transmission and Pathogenesis","volume":"41","author":"Harrison","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1053\/j.gastro.2020.02.055","article-title":"Evidence for Gastrointestinal Infection of SARS-CoV-2","volume":"158","author":"Xiao","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1053\/j.gastro.2020.04.008","article-title":"High Prevalence of Concurrent Gastrointestinal Manifestations in Patients With Severe Acute Respiratory Syndrome Coronavirus 2: Early Experience From California","volume":"159","author":"Cholankeril","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.gastro.2003.08.001","article-title":"Enteric Involvement of Severe Acute Respiratory Syndrome-Associated Coronavirus Infection","volume":"125","author":"Leung","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"659","DOI":"10.3389\/fneur.2020.00659","article-title":"Potential of SARS-CoV-2 to Cause CNS Infection: Biologic Fundamental and Clinical Experience","volume":"11","author":"Huang","year":"2020","journal-title":"Front. 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