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

• Published in: eLife Vol. 10
• Main Authors: Ma, Jiajia, Scott, Claire A, Ho, Ying Na, Mahabaleshwar, Harsha, Marsay, Katherine S, Zhang, Changqing, Teow, Christopher KJ, Ng, Ser Sue, Zhang, Weibin, Tergaonkar, Vinay, Partridge, Lynda J, Roy, Sudipto, Amaya, Enrique, Carney, Tom J
• Format: Journal Article
• Language: English
• Published: Cambridge eLife Science Publications, Ltd 24.06.2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adherens junctions; Apoptosis; Cell Biology; Development and progression; Epithelial cells; Genetics and Genomics; Hai1; Hydrogen peroxide; Inflammation; Inositol; Inositol 1,4,5-trisphosphate receptors; MAP kinase; Matriptase; Mutants; Mutation; Neutrophils; NF-κB protein; Par2; Phenotypes; Proteases; Proteins; RSK; Signal transduction; California
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.66596

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 H.sub.2O.sub.2, Nf[kappa]B signalling, and IP.sub.3R -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.