IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-35590-x.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-35590-x
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-35590-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Yunlong Cao & Jing Wang & Fanchong Jian & Tianhe Xiao & Weiliang Song & Ayijiang Yisimayi & Weijin Huang & Qianqian Li & Peng Wang & Ran An & Jing Wang & Yao Wang & Xiao Niu & Sijie Yang & Hui Liang &, 2022. "Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies," Nature, Nature, vol. 602(7898), pages 657-663, February.
    2. Jun Lan & Jiwan Ge & Jinfang Yu & Sisi Shan & Huan Zhou & Shilong Fan & Qi Zhang & Xuanling Shi & Qisheng Wang & Linqi Zhang & Xinquan Wang, 2020. "Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor," Nature, Nature, vol. 581(7807), pages 215-220, May.
    3. Xuanming Guo & Pallavi Asthana & Susma Gurung & Shuo Zhang & Sheung Kin Ken Wong & Samane Fallah & Chi Fung Willis Chow & Sijia Che & Lixiang Zhai & Zening Wang & Xin Ge & Zhixin Jiang & Jiayan Wu & Y, 2022. "Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Sonu Kumar & Boris I Ratnikov & Marat D Kazanov & Jeffrey W Smith & Piotr Cieplak, 2015. "CleavPredict: A Platform for Reasoning about Matrix Metalloproteinases Proteolytic Events," PLOS ONE, Public Library of Science, vol. 10(5), pages 1-19, May.
    5. Donald J. Benton & Antoni G. Wrobel & Pengqi Xu & Chloë Roustan & Stephen R. Martin & Peter B. Rosenthal & John J. Skehel & Steven J. Gamblin, 2020. "Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion," Nature, Nature, vol. 588(7837), pages 327-330, December.
    6. Sandile Cele & Laurelle Jackson & David S. Khoury & Khadija Khan & Thandeka Moyo-Gwete & Houriiyah Tegally & James Emmanuel San & Deborah Cromer & Cathrine Scheepers & Daniel G. Amoako & Farina Karim , 2022. "Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization," Nature, Nature, vol. 602(7898), pages 654-656, February.
    7. Delphine Planas & Nell Saunders & Piet Maes & Florence Guivel-Benhassine & Cyril Planchais & Julian Buchrieser & William-Henry Bolland & Françoise Porrot & Isabelle Staropoli & Frederic Lemoine & Hélè, 2022. "Considerable escape of SARS-CoV-2 Omicron to antibody neutralization," Nature, Nature, vol. 602(7898), pages 671-675, February.
    8. Jian Shang & Gang Ye & Ke Shi & Yushun Wan & Chuming Luo & Hideki Aihara & Qibin Geng & Ashley Auerbach & Fang Li, 2020. "Structural basis of receptor recognition by SARS-CoV-2," Nature, Nature, vol. 581(7807), pages 221-224, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Cai He & Jingyun Yang & Weiqi Hong & Zimin Chen & Dandan Peng & Hong Lei & Aqu Alu & Xuemei He & Zhenfei Bi & Xiaohua Jiang & Guowen Jia & Yun Yang & Yanan Zhou & Wenhai Yu & Cong Tang & Qing Huang & , 2022. "A self-assembled trimeric protein vaccine induces protective immunity against Omicron variant," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Tomohiro Takano & Takashi Sato & Ryutaro Kotaki & Saya Moriyama & Shuetsu Fukushi & Masahiro Shinoda & Kiyomi Kabasawa & Nagashige Shimada & Mio Kousaka & Yu Adachi & Taishi Onodera & Kazutaka Terahar, 2023. "Heterologous SARS-CoV-2 spike protein booster elicits durable and broad antibody responses against the receptor-binding domain," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Lei Wang & Zhiwei Wu & Zhifang Ying & Minjie Li & Yuansheng Hu & Qun Shu & Jing Li & Huixian Wang & Hengming Zhang & Wenbin Jiao & Lin Wang & Yuliang Zhao & Qiang Gao, 2022. "Safety and immunogenicity following a homologous booster dose of CoronaVac in children and adolescents," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    4. Zhennan Zhao & Jingya Zhou & Mingxiong Tian & Min Huang & Sheng Liu & Yufeng Xie & Pu Han & Chongzhi Bai & Pengcheng Han & Anqi Zheng & Lutang Fu & Yuanzhu Gao & Qi Peng & Ying Li & Yan Chai & Zengyua, 2022. "Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Katherine U. Gaynor & Marina Vaysburd & Maximilian A. J. Harman & Anna Albecka & Phillip Jeffrey & Paul Beswick & Guido Papa & Liuhong Chen & Donna Mallery & Brian McGuinness & Katerine Rietschoten & , 2023. "Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Chihiro Motozono & Mako Toyoda & Toong Seng Tan & Hiroshi Hamana & Yoshihiko Goto & Yoshiki Aritsu & Yusuke Miyashita & Hiroyuki Oshiumi & Kimitoshi Nakamura & Seiji Okada & Keiko Udaka & Mizuki Kitam, 2022. "The SARS-CoV-2 Omicron BA.1 spike G446S mutation potentiates antiviral T-cell recognition," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    7. Yifan Wang & Caixuan Liu & Chao Zhang & Yanxing Wang & Qin Hong & Shiqi Xu & Zuyang Li & Yong Yang & Zhong Huang & Yao Cong, 2022. "Structural basis for SARS-CoV-2 Delta variant recognition of ACE2 receptor and broadly neutralizing antibodies," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    8. Leander Witte & Viren A. Baharani & Fabian Schmidt & Zijun Wang & Alice Cho & Raphael Raspe & Camila Guzman-Cardozo & Frauke Muecksch & Marie Canis & Debby J. Park & Christian Gaebler & Marina Caskey , 2023. "Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    9. Gang Ye & Bin Liu & Fang Li, 2022. "Cryo-EM structure of a SARS-CoV-2 omicron spike protein ectodomain," Nature Communications, Nature, vol. 13(1), pages 1-7, December.
    10. Taha Y. Taha & Irene P. Chen & Jennifer M. Hayashi & Takako Tabata & Keith Walcott & Gabriella R. Kimmerly & Abdullah M. Syed & Alison Ciling & Rahul K. Suryawanshi & Hannah S. Martin & Bryan H. Bach , 2023. "Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    11. Haisheng Yu & Banghui Liu & Yudi Zhang & Xijie Gao & Qian Wang & Haitao Xiang & Xiaofang Peng & Caixia Xie & Yaping Wang & Peiyu Hu & Jingrong Shi & Quan Shi & Pingqian Zheng & Chengqian Feng & Guofan, 2023. "Somatically hypermutated antibodies isolated from SARS-CoV-2 Delta infected patients cross-neutralize heterologous variants," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    12. Emanuele Andreano & Ida Paciello & Silvia Marchese & Lorena Donnici & Giulio Pierleoni & Giulia Piccini & Noemi Manganaro & Elisa Pantano & Valentina Abbiento & Piero Pileri & Linda Benincasa & Ginevr, 2022. "Anatomy of Omicron BA.1 and BA.2 neutralizing antibodies in COVID-19 mRNA vaccinees," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    13. Zhennan Zhao & Yufeng Xie & Bin Bai & Chunliang Luo & Jingya Zhou & Weiwei Li & Yumin Meng & Linjie Li & Dedong Li & Xiaomei Li & Xiaoxiong Li & Xiaoyun Wang & Junqing Sun & Zepeng Xu & Yeping Sun & W, 2023. "Structural basis for receptor binding and broader interspecies receptor recognition of currently circulating Omicron sub-variants," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    14. Rajeshwer S. Sankhala & Kerri G. Lal & Jaime L. Jensen & Vincent Dussupt & Letzibeth Mendez-Rivera & Hongjun Bai & Lindsay Wieczorek & Sandra V. Mayer & Michelle Zemil & Danielle A. Wagner & Samantha , 2024. "Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    15. Xiaolei Wang & Terrence Tsz-Tai Yuen & Ying Dou & Jingchu Hu & Renhao Li & Zheng Zeng & Xuansheng Lin & Huarui Gong & Celia Hoi-Ching Chan & Chaemin Yoon & Huiping Shuai & Deborah Tip-Yin Ho & Ivan Fa, 2023. "Vaccine-induced protection against SARS-CoV-2 requires IFN-γ-driven cellular immune response," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    16. Oskar Staufer & Kapil Gupta & Jochen Estebano Hernandez Bücher & Fabian Kohler & Christian Sigl & Gunjita Singh & Kate Vasileiou & Ana Yagüe Relimpio & Meline Macher & Sebastian Fabritz & Hendrik Diet, 2022. "Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    17. Peter Radvak & Hyung-Joon Kwon & Martina Kosikova & Uriel Ortega-Rodriguez & Ruoxuan Xiang & Je-Nie Phue & Rong-Fong Shen & James Rozzelle & Neeraj Kapoor & Taylor Rabara & Jeff Fairman & Hang Xie, 2021. "SARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    18. Alief Moulana & Thomas Dupic & Angela M. Phillips & Jeffrey Chang & Serafina Nieves & Anne A. Roffler & Allison J. Greaney & Tyler N. Starr & Jesse D. Bloom & Michael M. Desai, 2022. "Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    19. Laurent Renia & Yun Shan Goh & Angeline Rouers & Nina Bert & Wan Ni Chia & Jean-Marc Chavatte & Siew‐Wai Fong & Zi Wei Chang & Nicole Ziyi Zhuo & Matthew Zirui Tay & Yi-Hao Chan & Chee Wah Tan & Nicho, 2022. "Lower vaccine-acquired immunity in the elderly population following two-dose BNT162b2 vaccination is alleviated by a third vaccine dose," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    20. Nina Breinholt Stærke & Joanne Reekie & Henrik Nielsen & Thomas Benfield & Lothar Wiese & Lene Surland Knudsen & Mette Brouw Iversen & Kasper Iversen & Kamille Fogh & Jacob Bodilsen & Maria Ruwald Juh, 2022. "Levels of SARS-CoV-2 antibodies among fully vaccinated individuals with Delta or Omicron variant breakthrough infections," Nature Communications, Nature, vol. 13(1), pages 1-8, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35590-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.