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
  • Calcium/metabolism
  • Serine Endopeptidases/genetics
  • Serine Endopeptidases/metabolism*
  • Inflammation/metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11/genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11/metabolism*
  • Enzyme Activation
  • Hydrogen Peroxide
  • Calcium Signaling
  • Animals, Genetically Modified
  • DNA/genetics
  • RNA/genetics
  • Polymerase Chain Reaction
  • Animals
  • Zebrafish
  • Gene Expression Regulation, Enzymologic/drug effects
  • Mutation
  • Peptides, Cyclic
  • Embryo, Nonmammalian
  • Neutrophils/physiology
(all 20)
PubMed
34165081 Full text @ Elife
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
Figures
Figure Gallery (20 images) / 2
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
fr26
    		Point Mutation
    hi2217TgTransgenic Insertion
    i114TgTransgenic Insertion
      lkc2TgTransgenic Insertion
        nc1TgTransgenic Insertion
          sq10
            		Insertion
            sq16TgTransgenic Insertion
              sq304
                		Small Deletion
                t419
                  		Point Mutation
                  ti251
                    		Unknown
                    1 - 10 of 11
                    Show
                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    Target Reagent Reagent Type
                    duoxMO1-duoxMRPHLNO
                    ikbkgTALEN1-ikbkgTALEN
                    tp53MO4-tp53MRPHLNO
                    1 - 3 of 3
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                    Fish
                    No data available
                    Antibodies
                    Name Type Antigen Genes Isotypes Host Organism
                    Ab1-rps6ka1polyclonal
                      		Rabbit
                      Ab1-tp63monoclonalIgG2aMouse
                      Ab2-cdh1monoclonal
                        		IgG2aMouse
                        Ab3-GFPpolyclonalIgGRabbit
                        Ab9-mapkmonoclonal
                          		IgGRabbit
                          Ab13-mapkpolyclonal
                            		Rabbit
                            Ab14-ctnnbpolyclonal
                              		IgGRabbit
                              Ab16-GFPpolyclonalIgYChicken
                              1 - 8 of 8
                              Show
                              Orthology
                              No data available
                              Engineered Foreign Genes
                              Marker Marker Type Name
                              EGFPEFGEGFP
                              GCaMPEFGGCaMP
                              GFPEFGGFP
                              mCherryEFGmCherry
                              TomatoEFGTomato
                              1 - 5 of 5
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                              Mapping
                              No data available
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                              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:.