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Compared with influenza virus and paramyxovirus membrane fusion proteins, the cleavage activation mechanism of coronavirus S protein is much more complex. The S protein has two cleavage sites (S1\/S2 and S2\u2032), and the cleavage motif for furin protease at the S1\/S2 site that results from a unique four\u2010amino acid insertion is one of the distinguishing features of SARS\u2010CoV\u20102. The viral particle incorporates the S protein, which has already undergone S1\/S2 cleavage by furin, and then undergoes further cleavage at the S2\u2032 site, mediated by the type II transmembrane serine protease transmembrane protease serine 2 (TMPRSS2), after binding to the receptor angiotensin\u2010converting enzyme 2 (ACE2) to facilitate membrane fusion at the plasma membrane. In addition, SARS\u2010CoV\u20102 can enter the cell by endocytosis and be proteolytically activated by cathepsin L, although this is not a major mode of SARS\u2010CoV\u20102 infection. SARS\u2010CoV\u20102 variants with enhanced infectivity have been emerging throughout the ongoing pandemic, and there is a close relationship between enhanced infectivity and changes in S protein cleavability. All four variants of concern carry the D614G mutation, which indirectly enhances S1\/S2 cleavability by furin. The P681R mutation of the delta variant directly increases S1\/S2 cleavability, enhancing membrane fusion and SARS\u2010CoV\u20102 virulence. Changes in S protein cleavability can significantly impact viral infectivity, tissue tropism, and virulence. Understanding these mechanisms is critical to counteracting the coronavirus pandemic.<\/jats:p>","DOI":"10.1111\/1348-0421.12945","type":"journal-article","created":{"date-parts":[[2021,9,25]],"date-time":"2021-09-25T04:16:31Z","timestamp":1632543391000},"page":"15-23","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":187,"title":["Proteolytic activation of SARS\u2010CoV\u20102 spike protein"],"prefix":"10.1111","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8194-7727","authenticated-orcid":false,"given":"Makoto","family":"Takeda","sequence":"first","affiliation":[{"name":"Department of Virology 3 National Institute of Infectious Diseases  Tokyo 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