Altered host protease determinants for SARS-CoV-2 Omicron Journal Article


Authors: Chan, J. F. W.; Huang, X.; Hu, B.; Chai, Y.; Shi, H.; Zhu, T.; Yuen, T. T. T.; Liu, Y.; Liu, H.; Shi, J.; Wen, L.; Shuai, H.; Hou, Y.; Yoon, C.; Cai, J. P.; Zhang, A. J.; Zhou, J.; Yin, F.; Yuan, S.; Zhang, B. Z.; Brindley, M. A.; Shi, Z. L.; Yuen, K. Y.; Chu, H.
Article Title: Altered host protease determinants for SARS-CoV-2 Omicron
Abstract: Successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires proteolytic cleavage of the viral spike protein. While the role of the host transmembrane protease serine 2 in SARS-CoV-2 infection is widely recognized, the involvement of other proteases capable of facilitating SARS-CoV-2 entry remains incompletely explored. Here, we show that multiple members from the membrane-type matrix metalloproteinase (MT-MMP) and a disintegrin and metalloproteinase families can mediate SARS-CoV-2 entry. Inhibition of MT-MMPs significantly reduces SARS-CoV-2 replication in vitro and in vivo. Mechanistically, we show that MT-MMPs can cleave SARS-CoV-2 spike and angiotensin-converting enzyme 2 and facilitate spike-mediated fusion. We further demonstrate that Omicron BA.1 has an increased efficiency on MT-MMP usage, while an altered efficiency on transmembrane serine protease usage for virus entry compared with that of ancestral SARS-CoV-2. These results reveal additional protease determinants for SARS-CoV-2 infection and enhance our understanding on the biology of coronavirus entry.
Keywords: metabolism; protein degradation; peptide hydrolases; metalloproteinase; peptide hydrolase; virus entry; metalloproteases; proteolysis; virus internalization; humans; human; covid-19; sars-cov-2
Journal Title: Science Advances
Volume: 9
Issue: 3
ISSN: 2375-2548
Publisher: Amer Assoc Advancement Science  
Date Published: 2023-01-20
Start Page: eadd3867
Language: English
DOI: 10.1126/sciadv.add3867
PUBMED: 36662861
PROVIDER: scopus
PMCID: PMC9858505
DOI/URL:
Notes: Article -- Export Date: 1 March 2023 -- Source: Scopus
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  1. Hongyu Shi
    13 Shi