PUBLICATION
Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX
- Authors
- Ma, J., Scott, C.A., Ho, Y.N., Mahabaleshwar, H., Marsay, K.S., Zhang, C., Teow, C.K., Ng, S.S., Zhang, W., Tergaonkar, V., Partridge, L.J., Roy, S., Amaya, E., Carney, T.J.
- ID
- ZDB-PUB-210625-9
- Date
- 2021
- Source
- eLIFE 10: (Journal)
- Registered Authors
- Carney, Tom, Mahabaleshwar, Harsha, Roy, Sudipto
- Keywords
- cell biology, genetics, genomics, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Calcium/metabolism
- Calcium Signaling
- DNA/genetics
- Embryo, Nonmammalian
- Enzyme Activation
- GTP-Binding Protein alpha Subunits, Gq-G11/genetics
- GTP-Binding Protein alpha Subunits, Gq-G11/metabolism*
- Gene Expression Regulation, Enzymologic/drug effects
- Hydrogen Peroxide
- Inflammation/metabolism
- Mutation
- Neutrophils/physiology
- Peptides, Cyclic
- Polymerase Chain Reaction
- RNA/genetics
- Serine Endopeptidases/genetics
- Serine Endopeptidases/metabolism*
- Zebrafish
- PubMed
- 34165081 Full text @ Elife
Citation
Ma, J., Scott, C.A., Ho, Y.N., Mahabaleshwar, H., Marsay, K.S., Zhang, C., Teow, C.K., Ng, S.S., Zhang, W., Tergaonkar, V., Partridge, L.J., Roy, S., Amaya, E., Carney, T.J. (2021) Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX. eLIFE. 10:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping