Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX

  1. Jiajia Ma
  2. Claire A Scott
  3. Ying Na Ho
  4. Harsha Mahabaleshwar
  5. Katherine S Marsay
  6. Changqing Zhang
  7. Christopher KJ Teow
  8. Ser Sue Ng
  9. Weibin Zhang
  10. Vinay Tergaonkar
  11. Lynda J Partridge
  12. Sudipto Roy
  13. Enrique Amaya
  14. Tom J Carney  Is a corresponding author
  1. Nanyang Technological University, Singapore
  2. A*STAR (Agency for Science, Technology and Research), Singapore
  3. Institite of molecular and cell biology, Singapore
  4. University of Sheffield, United Kingdom
  5. University of Manchester, United Kingdom

Abstract

Epithelial tissues are primed to respond to insults by activating epithelial cell motility and rapid inflammation. Such responses are also elicited upon overexpression of the membrane bound protease, Matriptase, or mutation of its inhibitor, Hai1. Unrestricted Matriptase activity also predisposes to carcinoma. How Matriptase leads to these cellular outcomes is unknown. We demonstrate that zebrafish hai1a mutants show increased H2O2, NfkB signalling, and IP3R -mediated calcium flashes, and that these promote inflammation, but do not generate epithelial cell motility. In contrast, inhibition of the Gq subunit in hai1a mutants rescues both the inflammation and epithelial phenotypes, with the latter recapitulated by the DAG analogue, PMA. We demonstrate that hai1a has elevated MAPK pathway activity, inhibition of which rescues the epidermal defects. Finally, we identify RSK kinases as MAPK targets disrupting adherens junctions in hai1a mutants. Our work maps novel signalling cascades mediating the potent effects of Matriptase on epithelia, with implications for tissue damage response and carcinoma progression.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Jiajia Ma

    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  2. Claire A Scott

    Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Ying Na Ho

    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. Harsha Mahabaleshwar

    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Katherine S Marsay

    Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Changqing Zhang

    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Christopher KJ Teow

    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  8. Ser Sue Ng

    Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  9. Weibin Zhang

    Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  10. Vinay Tergaonkar

    Cancer Genetics and Therapeutics, Institite of molecular and cell biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  11. Lynda J Partridge

    Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Sudipto Roy

    Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  13. Enrique Amaya

    Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Tom J Carney

    Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
    For correspondence
    tcarney@ntu.edu.sg
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2371-1924

Funding

Ministry of Education - Singapore (2015-T1-001-035)

  • Jiajia Ma
  • Tom J Carney

Ministry of Education - Singapore (MOE2016-T3-1-005)

  • Harsha Mahabaleshwar

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Fish were housed at the IMCB and the NTU zebrafish facilities under IACUC numbers #140924 and #A18002 respectively, and according to the guidelines of the National Advisory Committee for Laboratory Animal Research. Approval was provided by the Institutional Animal Care and Use Committees of the Biological Resource Centre (IMCB) and NTU according to Agri-Food and Veterinary Authority (AVA) Rules and the National Advisory Committee for Laboratory Animal Research (NACLAR) requirments.

Copyright

© 2021, Ma et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,085
    views
  • 227
    downloads
  • 5
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jiajia Ma
  2. Claire A Scott
  3. Ying Na Ho
  4. Harsha Mahabaleshwar
  5. Katherine S Marsay
  6. Changqing Zhang
  7. Christopher KJ Teow
  8. Ser Sue Ng
  9. Weibin Zhang
  10. Vinay Tergaonkar
  11. Lynda J Partridge
  12. Sudipto Roy
  13. Enrique Amaya
  14. Tom J Carney
(2021)
Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX
eLife 10:e66596.
https://doi.org/10.7554/eLife.66596

Share this article

https://doi.org/10.7554/eLife.66596

Further reading

    1. Cell Biology
    Yajun Zhai, Peiyi Liu ... Gongzheng Hu
    Research Article

    Discovering new strategies to combat the multidrug-resistant bacteria constitutes a major medical challenge of our time. Previously, artesunate (AS) has been reported to exert antibacterial enhancement activity in combination with β-lactam antibiotics via inhibition of the efflux pump AcrB. However, combination of AS and colistin (COL) revealed a weak synergistic effect against a limited number of strains, and few studies have further explored its possible mechanism of synergistic action. In this article, we found that AS and EDTA could strikingly enhance the antibacterial effects of COL against mcr-1- and mcr-1+ Salmonella strains either in vitro or in vivo, when used in triple combination. The excellent bacteriostatic effect was primarily related to the increased cell membrane damage, accumulation of toxic compounds and inhibition of MCR-1. The potential binding sites of AS to MCR-1 (THR283, SER284, and TYR287) were critical for its inhibition of MCR-1 activity. Additionally, we also demonstrated that the CheA of chemosensory system and virulence-related protein SpvD were critical for the bacteriostatic synergistic effects of the triple combination. Selectively targeting CheA, SpvD, or MCR using the natural compound AS could be further investigated as an attractive strategy for the treatment of Salmonella infection. Collectively, our work opens new avenues toward the potentiation of COL and reveals an alternative drug combination strategy to overcome COL-resistant bacterial infections.

    1. Cell Biology
    2. Genetics and Genomics
    Adam D Longhurst, Kyle Wang ... David P Toczyski
    Tools and Resources

    Progression through the G1 phase of the cell cycle is the most highly regulated step in cellular division. We employed a chemogenetic approach to discover novel cellular networks that regulate cell cycle progression. This approach uncovered functional clusters of genes that altered sensitivity of cells to inhibitors of the G1/S transition. Mutation of components of the Polycomb Repressor Complex 2 rescued proliferation inhibition caused by the CDK4/6 inhibitor palbociclib, but not to inhibitors of S phase or mitosis. In addition to its core catalytic subunits, mutation of the PRC2.1 accessory protein MTF2, but not the PRC2.2 protein JARID2, rendered cells resistant to palbociclib treatment. We found that PRC2.1 (MTF2), but not PRC2.2 (JARID2), was critical for promoting H3K27me3 deposition at CpG islands genome-wide and in promoters. This included the CpG islands in the promoter of the CDK4/6 cyclins CCND1 and CCND2, and loss of MTF2 lead to upregulation of both CCND1 and CCND2. Our results demonstrate a role for PRC2.1, but not PRC2.2, in antagonizing G1 progression in a diversity of cell linages, including chronic myeloid leukemia (CML), breast cancer, and immortalized cell lines.