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- Title
Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2.
- Authors
Guo, Xuanming; Cao, Jianli; Cai, Jian-Piao; Wu, Jiayan; Huang, Jiangang; Asthana, Pallavi; Wong, Sheung Kin Ken; Ye, Zi-Wei; Gurung, Susma; Zhang, Yijing; Wang, Sheng; Wang, Zening; Ge, Xin; Kwan, Hiu Yee; Lyu, Aiping; Chan, Kui Ming; Wong, Nathalie; Huang, Jiandong; Zhou, Zhongjun; Bian, Zhao-Xiang
- 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 solACE218-706 that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE218-706 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.The role of soluble angiotensin converting enzyme 2 (sACE2) in SARS-CoV-2 infection is not well understood. Here, authors show that membrane type 1 matrix metalloproteinase (MT1-MMP) releases sACE2 to promote SARS-CoV-2 cell entry in vitro and in vivo, and the upregulation of MT1-MMP may contribute to increased susceptibility to SARS-CoV-2 infection in ageing.
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-35590-x