Huang, I-ChuehBosch, Berend JanLi, FangLi, WenhuiLee, Kyoung HoaGhiran, SorinaVasilieva, NatalyaDermody, Terence S.Harrison, Stephen C.Dormitzer, Philip R.Farzan, MichaelRottier, Peter J. M.Choe, Hyeryun2019-10-132006Huang, I-Chueh, Berend Jan Bosch, Fang Li, Wenhui Li, Kyoung Hoa Lee, Sorina Ghiran, Natalya Vasilieva, et al. 2006. “SARS Coronavirus, but Not Human Coronavirus NL63, Utilizes Cathepsin L to Infect ACE2-Expressing Cells.” Journal of Biological Chemistry 281 (6): 3198–3203. doi:10.1074/jbc.M508381200.0021-92581083-351Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41542807Viruses require specific cellular receptors to infect their target cells. Angiotensin-converting enzyme 2 ( ACE2) is a cellular receptor for two divergent coronaviruses, SARS coronavirus (SARS-CoV) and human coronavirus NL63 (HCoV-NL63). In addition to host-cell receptors, lysosomal cysteine proteases are required for productive infection by some viruses. Here we show that SARS-CoV, but not HCoV-NL63, utilizes the enzymatic activity of the cysteine protease cathepsin L to infect ACE2-expressing cells. Inhibitors of cathepsin L blocked infection by SARS-CoV and by a retrovirus pseudotyped with the SARS-CoV spike ( S) protein but not infection by HCoV-NL63 or a retrovirus pseudotyped with the HCoV-NL63 S protein. Expression of exogenous cathepsin L substantially enhanced infection mediated by the SARS-CoV S protein and by filovirus GP proteins but not by the HCoV-NL63 S protein or the vesicular stomatitis virus G protein. Finally, an inhibitor of endosomal acidification had substantially less effect on infection mediated by the HCoV-NL63 S protein than on that mediated by the SARS-CoV S protein. Our data indicate that two coronaviruses that utilize a common receptor nonetheless enter cells through distinct mechanisms.en-USJournal Article2019-10-1310.1074/jbc.M508381200