Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2

Xuanming Guo, Jianli Cao, Jian Piao Cai, Jiayan Wu, Jiangang Huang, Pallavi Asthana, Sheung Kin Ken Wong, Zi Wei Ye, Susma Gurung, Yijing Zhang, Sheng Wang, Zening Wang, Xin Ge, Hiu Yee Kwan, Aiping Lyu, Kui Ming Chan, Nathalie Wong, Jiandong Huang, Zhongjun Zhou, Zhao Xiang BianShuofeng Yuan*, Hoi Leong Xavier Wong*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

7 Citations (Scopus)


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.

Original languageEnglish
Article number7907
Number of pages17
JournalNature Communications
Publication statusPublished - 23 Dec 2022

Scopus Subject Areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)


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