Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX
- Nanyang Technological University, Singapore
- A*STAR (Agency for Science, Technology and Research), Singapore
- Institite of molecular and cell biology, Singapore
- University of Sheffield, United Kingdom
- 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
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.
Reviewing Editor
- Jonathan A Cooper, Fred Hutchinson Cancer Research Center, United States
Publication history
- Received: January 15, 2021
- Accepted: June 23, 2021
- Accepted Manuscript published: June 24, 2021 (version 1)
- Version of Record published: July 20, 2021 (version 2)
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.
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Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX
eLife 10:e66596.
https://doi.org/10.7554/eLife.66596
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