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 Bian, Shuofeng Yuan () and Hoi Leong Xavier Wong ()
Additional contact information
Xuanming Guo: Hong Kong Baptist University
Jianli Cao: The University of Hong Kong
Jian-Piao Cai: The University of Hong Kong
Jiayan Wu: Hong Kong Baptist University
Jiangang Huang: School of Pharmaceutical Sciences, Xiamen University
Pallavi Asthana: Hong Kong Baptist University
Sheung Kin Ken Wong: The University of Hong Kong
Zi-Wei Ye: The University of Hong Kong
Susma Gurung: Hong Kong Baptist University
Yijing Zhang: Hong Kong Baptist University
Sheng Wang: Jinhua Guangfu Hospital
Zening Wang: University of Texas Health Science Center at Houston
Xin Ge: University of Texas Health Science Center at Houston
Hiu Yee Kwan: Hong Kong Baptist University
Aiping Lyu: Hong Kong Baptist University
Kui Ming Chan: City University of Hong Kong
Nathalie Wong: The Chinese University of Hong Kong, Prince of Wales Hospital, N.T.
Jiandong Huang: The University of Hong Kong
Zhongjun Zhou: The University of Hong Kong
Zhao-Xiang Bian: Hong Kong Baptist University
Shuofeng Yuan: The University of Hong Kong
Hoi Leong Xavier Wong: Hong Kong Baptist University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-35590-x

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