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

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, Yuan, Shuofeng, Wong, Hoi Leong Xavier·2022·Nature Communications
DOI 10.1038/s41467-022-35590-xPMC PMC9780620
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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.

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  1. Yan, R. et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 367, 1444–1448 (2020). · DOI
  2. Shang, J. et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 581, 221–224 (2020). · DOI · Paper page
  3. Lan, J. et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581, 215–220 (2020). · DOI · Paper page
  4. Glowacka, I. et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J. Virol. 85, 4122–4134 (2011). · DOI
  5. Shulla, A. et al. A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J. Virol. 85, 873–882 (2011). · DOI
  6. Huang, I. C. et al. SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. J. Biol. Chem. 281, 3198–3203 (2006). · DOI
  7. Simmons, G. et al. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc. Natl Acad. Sci. 102, 11876–11881 (2005). · DOI
  8. Hoffmann, M. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181, 271–280.e278 (2020). · DOI · Paper page
  9. Inoue, Y. et al. Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted. J. Virol. 81, 8722–8729 (2007). · DOI · Paper page
  10. Schoeman, D. & Fielding, B. C. Coronavirus envelope protein: current knowledge. Virol. J. 16, 69 (2019). · DOI
  11. Yeung, M. L. et al. Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system. Cell 184, 2212–2228.e2212 (2021). · DOI
  12. Haga, S. et al. Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry. Proc. Natl Acad. Sci. 105, 7809–7814 (2008). · DOI
  13. Hassler, L. et al. A novel soluble ACE2 protein totally protects from lethal disease caused by SARS-CoV-2 infection. bioRxiv, https://doi.org/10.1101/2021.03.12.435191 (2021). · DOI
  14. Monteil, V. et al. Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2. Cell 181, 905–913.e907 (2020). · DOI · Paper page
  15. Wysocki, J. et al. A Novel Soluble ACE2 Variant with Prolonged Duration of Action Neutralizes SARS-CoV-2 Infection in Human Kidney Organoids. J. Am. Soc. Nephrol. https://doi.org/10.1681/ASN.2020101537 (2021). · DOI
  16. Zoufaly, A. et al. Human recombinant soluble ACE2 in severe COVID-19. Lancet Respir. Med 8, 1154–1158 (2020). · DOI
  17. Holmbeck, K. et al. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99, 81–92 (1999). · DOI · Paper page
  18. Zhou, Z. et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl Acad. Sci. 97, 4052–4057 (2000). · DOI · Paper page
  19. Chow, C. F. W. et al. Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nat. Metab. 4, 203–212 (2022). · DOI · Paper page
  20. Turunen, S. P., Tatti-Bugaeva, O. & Lehti, K. Membrane-type matrix metalloproteases as diverse effectors of cancer progression. Biochim Biophys. Acta Mol. Cell Res. 1864, 1974–1988 (2017). · DOI
  21. Chan, K. M. et al. MT1-MMP inactivates ADAM9 to regulate FGFR2 signaling and calvarial osteogenesis. Dev. Cell 22, 1176–1190 (2012). · DOI · Paper page
  22. Jin, G. et al. MT1-MMP cleaves Dll1 to negatively regulate Notch signalling to maintain normal B-cell development. EMBO J. 30, 2281–2293 (2011). · DOI · Paper page
  23. Wong, H. L. et al. MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis. Nat. Commun. 7, 10824 (2016). · DOI
  24. Kumar, S., Ratnikov, B. I., Kazanov, M. D., Smith, J. W. & Cieplak, P. CleavPredict: A Platform for Reasoning about Matrix Metalloproteinases Proteolytic Events. PLoS One. 10, e0127877 (2015). · DOI · Paper page
  25. Chua, R. L. et al. COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis. Nat. Biotechnol. 38, 970–979 (2020). · DOI · Paper page
  26. Trump, S. et al. Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19. Nat. Biotechnol. 39, 705–716 (2021). · DOI
  27. Loske, J. et al. Pre-activated antiviral innate immunity in the upper airways controls early SARS-CoV-2 infection in children. Nat Biotechnol, https://doi.org/10.1038/s41587-021-01037-9 (2021). · DOI
  28. Zou, X. et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 14, 185–192 (2020). · DOI · Paper page
  29. Schuler, B. A. et al. Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium. J Clin Invest. 131, https://doi.org/10.1172/JCI140766 (2021). · DOI
  30. Mills, R. J. et al. BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection. Cell 184, 2167–2182 e2122 (2021). · DOI
  31. Yang, L. et al. A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids. Cell Stem Cell. 27, 125–136.e127 (2020). · DOI
  32. Lamers, M. M. et al. An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells. EMBO J. 40, e105912 (2021). · DOI · Paper page
  33. Remacle, A. G. et al. Selective function-blocking monoclonal human antibody highlights the important role of membrane type-1 matrix metalloproteinase (MT1-MMP) in metastasis. Oncotarget 8, 2781–2799 (2017). · DOI
  34. Nam, D. H., Lee, K. B., Kruchowy, E., Pham, H. & Ge, X. Protease Inhibition Mechanism of Camelid-like Synthetic Human Antibodies. Biochemistry 59, 3802–3812 (2020). · DOI
  35. Nam, D. H., Rodriguez, C., Remacle, A. G., Strongin, A. Y. & Ge, X. Active-site MMP-selective antibody inhibitors discovered from convex paratope synthetic libraries. Proc. Natl Acad. Sci. 113, 14970–14975 (2016). · DOI
  36. Chakraborty, C., Sharma, A. R., Sharma, G., Bhattacharya, M. & Lee, S. S. SARS-CoV-2 causing pneumonia-associated respiratory disorder (COVID-19): diagnostic and proposed therapeutic options. Eur. Rev. Med Pharm. 24, 4016–4026 (2020).
  37. Zhou, F., Yu, T. & Du, R. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study (395, 1054, 2020). Lancet 395, 1038–1038 (2020). · DOI · Paper page
  38. Toth, M. et al. Complex pattern of membrane type 1 matrix metalloproteinase shedding. Regulation by autocatalytic cells surface inactivation of active enzyme. J. Biol. Chem. 277, 26340–26350 (2002). · DOI · Paper page
  39. Maisi, P. et al. Soluble membrane-type 1 matrix metalloproteinase (MT1-MMP) and gelatinase A (MMP-2) in induced sputum and bronchoalveolar lavage fluid of human bronchial asthma and bronchiectasis. APMIS 110, 771–782 (2002). · DOI · Paper page
  40. Li, H. et al. Immunological characterization of cell-surface and soluble forms of membrane type 1 matrix metalloproteinase in human breast cancer cells and in fibroblasts. Mol. Carcinog. 22, 84–94 (1998). · DOI
  41. Lukassen, S. et al. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J. 39, e105114 (2020). · DOI
  42. Guo, X. et al. Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor. Nat. Commun. 13, 3749 (2022). · DOI · Paper page
  43. Yang, Z. et al. Genetic Landscape of the ACE2 Coronavirus Receptor. Circulation, https://doi.org/10.1161/CIRCULATIONAHA.121.057888 (2022). · DOI
  44. Kornilov, S. A. et al. Plasma levels of soluble ACE2are associated with sex, Metabolic Syndrome, and its biomarkers in a large cohort, pointing to a possible mechanism for increased severity in COVID-19. Crit. Care. 24, 452 (2020). · DOI
  45. Wallentin, L. et al. Angiotensin-converting enzyme 2 (ACE2) levels in relation to risk factors for COVID-19 in two large cohorts of patients with atrial fibrillation. Eur. Heart J. 41, 4037–4046 (2020). · DOI
  46. Donoghue, M. et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ. Res. 87, E1–E9 (2000). · DOI · Paper page
  47. Jia, H. P. et al. Ectodomain shedding of angiotensin converting enzyme 2 in human airway epithelia. Am. J. Physiol. Lung Cell Mol. Physiol. 297, L84–L96 (2009). · DOI
  48. Lambert, D. W. et al. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J. Biol. Chem. 280, 30113–30119 (2005). · DOI
  49. Wong, H. L. et al. When MT1-MMP meets ADAMs. Cell Cycle 11, 2793–2798 (2012). · DOI
  50. Benton, D. J. et al. Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion. Nature 588, 327–330 (2020). · DOI
  51. Yamamoto, M. et al. Metalloproteinase-Dependent and TMPRSS2-Independent Cell Surface Entry Pathway of SARS-CoV-2 Requires the Furin Cleavage Site and the S2 Domain of Spike Protein. mBio 13, e0051922 (2022). · DOI
  52. Benlarbi, M. et al. Identification and differential usage of a host metalloproteinase entry pathway by SARS-CoV-2 Delta and Omicron. iScience, 105316, https://doi.org/10.1016/j.isci.2022.105316 (2022). · DOI
  53. Zhang, X. et al. SARS-CoV-2 Omicron strain exhibits potent capabilities for immune evasion and viral entrance. Signal Transduct. Target Ther. 6, 430 (2021). · DOI
  54. Cele, S. et al. Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization. Nature 602, 654–656 (2022). · DOI · Paper page
  55. Planas, D. et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature 602, 671–675 (2022). · DOI · Paper page
  56. Kormann, R. et al. Periostin Promotes Cell Proliferation and Macrophage Polarization to Drive Repair after AKI. J. Am. Soc. Nephrol. 31, 85–100 (2020). · DOI
  57. Park, E. J. et al. The Spike Glycoprotein of SARS-CoV-2 Binds to beta1 Integrins Expressed on the Surface of Lung Epithelial Cells. Viruses 13, https://doi.org/10.3390/v13040645 (2021). · DOI
  58. Yuan, S. et al. Viruses harness YxxO motif to interact with host AP2M1 for replication: A vulnerable broad-spectrum antiviral target. Sci. Adv. 6, eaba7910 (2020). · DOI

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Metadata

Authors
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., Bian, Z.-X., Yuan, S., & Wong, H. L. X.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-12-23
Volume
13
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-022-35590-x
PMC
PMC9780620
Cited by
25
References
13
Language
en
Licence
Funders
  • Research Grants Council, University Grants Committee (R4017-18, 12101019, 12102020)
  • Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (06170056, 08793626)
  • Natural Science Foundation of Guangdong Province (2021A1515011128)

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