Matriptase generates a tissue damage response via promoting Gq signalling, leading to RSK and DUOX activation

Ma, J.; Scott, C. A.; Ho, Y. N.; Marsay, K. S.; Zhang, C.; Teow, C. K. J.; Ng, S. S.; Zhang, W.; Tergaonkar, V.; Partridge, L. J.; Roy, S.; Amaya, E.; Carney, T. J.

doi:10.1101/2021.01.21.427549

bioRxiv · 10.1101/2021.01.21.427549

Matriptase generates a tissue damage response via promoting Gq signalling, leading to RSK and DUOX activation

Ma, J.·Scott, C. A.·Ho, Y. N.·Marsay, K. S.·Zhang, C.·Teow, C. K. J.·Ng, S. S.·Zhang, W.·Tergaonkar, V.·Partridge, L. J.·Roy, S.·Amaya, E.·Carney, T. J.

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Abstract

Tissues respond to damage by increasing inflammation and epithelial cell motility. How damage detection and responses are orchestrated is unclear. Overexpression of the membrane bound protease, Matriptase, or mutation of its inhibitor, Hai1, results in inflamed epithelia, in which cells have increased motility and are prone to carcinoma. How Matriptase leads to these cellular outcomes is unknown. We demonstrate that zebrafish hai1a mutants show increased H2O2, Nf{kappa}B 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 rescues both the hai1a inflammation and epithelial phenotypes, with the latter recapitulated by the DAG analogue, PMA. We demonstrate that hai1a has elevated pERK, inhibition of which rescues the epidermal defects. Finally, we identify RSK kinases as pERK 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.

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Ma, J., Scott, C. A., Ho, Y. N., Marsay, K. S., Zhang, C., Teow, C. K. J., Ng, S. S., Zhang, W., Tergaonkar, V., Partridge, L. J., Roy, S., Amaya, E., Carney, T. J.. 2021-01-21. Matriptase generates a tissue damage response via promoting Gq signalling, leading to RSK and DUOX activation. https://doi.org/10.1101/2021.01.21.427549

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