tetano
Editor, Senior Moderator
Nat Commun
. 2022 Dec 23;13(1):7907.
doi: 10.1038/s41467-022-35590-x.
Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2
Xuanming Guo[SUP] #[/SUP][SUP] 1 [/SUP], Jianli Cao[SUP] #[/SUP][SUP] 2 [/SUP], Jian-Piao Cai[SUP] #[/SUP][SUP] 3 [/SUP], Jiayan Wu[SUP] 1 [/SUP], Jiangang Huang[SUP] 4 [/SUP], Pallavi Asthana[SUP] 1 [/SUP], Sheung Kin Ken Wong[SUP] 5 [/SUP], Zi-Wei Ye[SUP] 2 [/SUP], Susma Gurung[SUP] 1 [/SUP], Yijing Zhang[SUP] 1 [/SUP], Sheng Wang[SUP] 6 [/SUP], Zening Wang[SUP] 7 [/SUP], Xin Ge[SUP] 7 [/SUP], Hiu Yee Kwan[SUP] 1 [/SUP], Aiping Lyu[SUP] 1 [/SUP], Kui Ming Chan[SUP] 8 [/SUP], Nathalie Wong[SUP] 9 [/SUP], Jiandong Huang[SUP] 5 [/SUP], Zhongjun Zhou[SUP] 5 [/SUP], Zhao-Xiang Bian[SUP] 10 [/SUP], Shuofeng Yuan[SUP] 11 [/SUP], Hoi Leong Xavier Wong[SUP] 12 [/SUP]
Affiliations
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung epithelium. Mechanistically, MT1-MMP directly cleaves memACE2 at M706-S to release solACE2[SUB]18-706[/SUB] that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE2[SUB]18-706[/SUB] enables SARS-CoV-2 infection in both non-permissive cells and naturally insusceptible C57BL/6 mice. Inhibition of MT1-MMP activities suppresses solACE2-directed entry of SARS-CoV-2 in human organoids and aged mice. Both solACE2 and circulating MT1-MMP are positively correlated in plasma of aged mice and humans. Our findings provide in vivo evidence demonstrating the contribution of ACE2 shedding to the etiology of COVID-19.
. 2022 Dec 23;13(1):7907.
doi: 10.1038/s41467-022-35590-x.
Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2
Xuanming Guo[SUP] #[/SUP][SUP] 1 [/SUP], Jianli Cao[SUP] #[/SUP][SUP] 2 [/SUP], Jian-Piao Cai[SUP] #[/SUP][SUP] 3 [/SUP], Jiayan Wu[SUP] 1 [/SUP], Jiangang Huang[SUP] 4 [/SUP], Pallavi Asthana[SUP] 1 [/SUP], Sheung Kin Ken Wong[SUP] 5 [/SUP], Zi-Wei Ye[SUP] 2 [/SUP], Susma Gurung[SUP] 1 [/SUP], Yijing Zhang[SUP] 1 [/SUP], Sheng Wang[SUP] 6 [/SUP], Zening Wang[SUP] 7 [/SUP], Xin Ge[SUP] 7 [/SUP], Hiu Yee Kwan[SUP] 1 [/SUP], Aiping Lyu[SUP] 1 [/SUP], Kui Ming Chan[SUP] 8 [/SUP], Nathalie Wong[SUP] 9 [/SUP], Jiandong Huang[SUP] 5 [/SUP], Zhongjun Zhou[SUP] 5 [/SUP], Zhao-Xiang Bian[SUP] 10 [/SUP], Shuofeng Yuan[SUP] 11 [/SUP], Hoi Leong Xavier Wong[SUP] 12 [/SUP]
Affiliations
- PMID: 36564389
- DOI: 10.1038/s41467-022-35590-x
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung epithelium. Mechanistically, MT1-MMP directly cleaves memACE2 at M706-S to release solACE2[SUB]18-706[/SUB] that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE2[SUB]18-706[/SUB] enables SARS-CoV-2 infection in both non-permissive cells and naturally insusceptible C57BL/6 mice. Inhibition of MT1-MMP activities suppresses solACE2-directed entry of SARS-CoV-2 in human organoids and aged mice. Both solACE2 and circulating MT1-MMP are positively correlated in plasma of aged mice and humans. Our findings provide in vivo evidence demonstrating the contribution of ACE2 shedding to the etiology of COVID-19.