tetano
Editor, Senior Moderator
Sci Adv
. 2023 Jan 20;9(3):eadd3867.
doi: 10.1126/sciadv.add3867. Epub 2023 Jan 20.
Altered host protease determinants for SARS-CoV-2 Omicron
Jasper Fuk-Woo Chan[SUP] 1 2 3 4 5 6 [/SUP], Xiner Huang[SUP] 1 [/SUP], Bingjie Hu[SUP] 1 [/SUP], Yue Chai[SUP] 1 [/SUP], Hongyu Shi[SUP] 7 [/SUP], Tianrenzheng Zhu[SUP] 1 [/SUP], Terrence Tsz-Tai Yuen[SUP] 1 [/SUP], Yuanchen Liu[SUP] 1 [/SUP], Huan Liu[SUP] 1 [/SUP], Jialu Shi[SUP] 1 [/SUP], Lei Wen[SUP] 1 [/SUP], Huiping Shuai[SUP] 1 [/SUP], Yuxin Hou[SUP] 1 [/SUP], Chaemin Yoon[SUP] 1 [/SUP], Jian-Piao Cai[SUP] 1 [/SUP], Anna Jinxia Zhang[SUP] 1 3 [/SUP], Jie Zhou[SUP] 1 [/SUP], Feifei Yin[SUP] 5 8 [/SUP], Shuofeng Yuan[SUP] 1 2 3 [/SUP], Bao-Zhong Zhang[SUP] 9 [/SUP], Melinda A Brindley[SUP] 10 [/SUP], Zheng-Li Shi[SUP] 11 [/SUP], Kwok-Yung Yuen[SUP] 1 2 3 4 5 6 [/SUP], Hin Chu[SUP] 1 2 3 [/SUP]
Affiliations
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.
. 2023 Jan 20;9(3):eadd3867.
doi: 10.1126/sciadv.add3867. Epub 2023 Jan 20.
Altered host protease determinants for SARS-CoV-2 Omicron
Jasper Fuk-Woo Chan[SUP] 1 2 3 4 5 6 [/SUP], Xiner Huang[SUP] 1 [/SUP], Bingjie Hu[SUP] 1 [/SUP], Yue Chai[SUP] 1 [/SUP], Hongyu Shi[SUP] 7 [/SUP], Tianrenzheng Zhu[SUP] 1 [/SUP], Terrence Tsz-Tai Yuen[SUP] 1 [/SUP], Yuanchen Liu[SUP] 1 [/SUP], Huan Liu[SUP] 1 [/SUP], Jialu Shi[SUP] 1 [/SUP], Lei Wen[SUP] 1 [/SUP], Huiping Shuai[SUP] 1 [/SUP], Yuxin Hou[SUP] 1 [/SUP], Chaemin Yoon[SUP] 1 [/SUP], Jian-Piao Cai[SUP] 1 [/SUP], Anna Jinxia Zhang[SUP] 1 3 [/SUP], Jie Zhou[SUP] 1 [/SUP], Feifei Yin[SUP] 5 8 [/SUP], Shuofeng Yuan[SUP] 1 2 3 [/SUP], Bao-Zhong Zhang[SUP] 9 [/SUP], Melinda A Brindley[SUP] 10 [/SUP], Zheng-Li Shi[SUP] 11 [/SUP], Kwok-Yung Yuen[SUP] 1 2 3 4 5 6 [/SUP], Hin Chu[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 36662861
- DOI: 10.1126/sciadv.add3867
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.