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; Hoi Leong Xavier Wong

doi:10.1038/s41467-022-35590-x

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 journal › Journal article › peer-review

9 Citations (Scopus)

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_18-706 that binds to the SARS-CoV-2 spike proteins (S), thus facilitating cell entry of SARS-CoV-2. Human solACE2_18-706 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 language	English
Article number	7907
Number of pages	17
Journal	Nature Communications
Volume	13
DOIs	https://doi.org/10.1038/s41467-022-35590-x
Publication status	Published - 23 Dec 2022

Scopus Subject Areas

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

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-022-35590-x

Cite this

Guo, X., Cao, J., Cai, J. P., Wu, J., Huang, J., Asthana, P., Wong, S. K. K., Ye, Z. W., Gurung, S., Zhang, Y., Wang, S., Wang, Z., Ge, X., Kwan, H. Y., Lyu, A., Chan, K. M., Wong, N., Huang, J., Zhou, Z., ... Wong, H. L. X. (2022). Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2. Nature Communications, 13, Article 7907. https://doi.org/10.1038/s41467-022-35590-x

@article{6f737bd070514312b5f45060dd7bc3b9,

title = "Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2",

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.",

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

note = "Funding Information: The presented work was kindly supported by General Research Fund (12101019 and 12102020; W.H.L.X.), Research Impact Fund (R4017-18; W.N.), Health and Medical Research Fund (06170056 and 08793626; W.H.L.X.), National Natural Science Fund (81802838; W.H.L.X.) and Guangdong Natural Science Foundation (2021A1515011128; W.H.L.X.). Publisher Copyright: {\textcopyright} The Author(s) 2022",

year = "2022",

month = dec,

day = "23",

doi = "10.1038/s41467-022-35590-x",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

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T1 - Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2

AU - Guo, Xuanming

AU - Cao, Jianli

AU - Cai, Jian Piao

AU - Wu, Jiayan

AU - Huang, Jiangang

AU - Asthana, Pallavi

AU - Wong, Sheung Kin Ken

AU - Ye, Zi Wei

AU - Gurung, Susma

AU - Zhang, Yijing

AU - Wang, Sheng

AU - Wang, Zening

AU - Ge, Xin

AU - Kwan, Hiu Yee

AU - Lyu, Aiping

AU - Chan, Kui Ming

AU - Wong, Nathalie

AU - Huang, Jiandong

AU - Zhou, Zhongjun

AU - Bian, Zhao Xiang

AU - Yuan, Shuofeng

AU - Wong, Hoi Leong Xavier

N1 - Funding Information: The presented work was kindly supported by General Research Fund (12101019 and 12102020; W.H.L.X.), Research Impact Fund (R4017-18; W.N.), Health and Medical Research Fund (06170056 and 08793626; W.H.L.X.), National Natural Science Fund (81802838; W.H.L.X.) and Guangdong Natural Science Foundation (2021A1515011128; W.H.L.X.). Publisher Copyright: © The Author(s) 2022

PY - 2022/12/23

Y1 - 2022/12/23

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-022-35590-x

DO - 10.1038/s41467-022-35590-x

M3 - Journal article

C2 - 36564389

AN - SCOPUS:85144636998

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

M1 - 7907

ER -

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

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