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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 K, 2022. "Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35590-x
    DOI: 10.1038/s41467-022-35590-x
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