Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/159382 |
| _version_ | 1826130689234305024 |
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| author | Ma, Jiajia Scott, Claire A. Ho, Ying Na Mahabaleshwar, Harsha Marsay, Katherine S. Zhang, Changqing Teow, Christopher K. J. Ng, Ser Sue Zhang, Weibin Tergaonkar, Vinay Partridge, Lynda J. Roy, Sudipto Amaya, Enrique Carney, Tom J. |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Ma, Jiajia Scott, Claire A. Ho, Ying Na Mahabaleshwar, Harsha Marsay, Katherine S. Zhang, Changqing Teow, Christopher K. J. Ng, Ser Sue Zhang, Weibin Tergaonkar, Vinay Partridge, Lynda J. Roy, Sudipto Amaya, Enrique Carney, Tom J. |
| author_sort | Ma, Jiajia |
| collection | NTU |
| description | 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, NfκB 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. |
| first_indexed | 2024-10-01T08:00:22Z |
| format | Journal Article |
| id | ntu-10356/159382 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T08:00:22Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1593822023-03-05T16:52:47Z Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX Ma, Jiajia Scott, Claire A. Ho, Ying Na Mahabaleshwar, Harsha Marsay, Katherine S. Zhang, Changqing Teow, Christopher K. J. Ng, Ser Sue Zhang, Weibin Tergaonkar, Vinay Partridge, Lynda J. Roy, Sudipto Amaya, Enrique Carney, Tom J. Lee Kong Chian School of Medicine (LKCMedicine) Institute of Molecular and Cell Biology, A*STAR Science::Medicine Epidermis Epithelia 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, NfκB 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. Ministry of Education (MOE) Published version This work was supported by the Singapore Ministry of Education (2015-T1-001-035 to Jiajia Ma & Tom J Carney and MOE2016-T3-1-005 to Harsha Mahabaleshwar). 2022-06-15T07:23:20Z 2022-06-15T07:23:20Z 2021 Journal Article Ma, J., Scott, C. A., Ho, Y. N., Mahabaleshwar, H., 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). Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX. ELife, 10, e66596-. https://dx.doi.org/10.7554/eLife.66596 2050-084X https://hdl.handle.net/10356/159382 10.7554/eLife.66596 34165081 2-s2.0-85109526108 10 e66596 en 2015-T1-001-035 MOE2016-T3-1-005 eLife © 2021 Ma et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. application/pdf |
| spellingShingle | Science::Medicine Epidermis Epithelia Ma, Jiajia Scott, Claire A. Ho, Ying Na Mahabaleshwar, Harsha Marsay, Katherine S. Zhang, Changqing Teow, Christopher K. J. Ng, Ser Sue Zhang, Weibin Tergaonkar, Vinay Partridge, Lynda J. Roy, Sudipto Amaya, Enrique Carney, Tom J. Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX |
| title | Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX |
| title_full | Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX |
| title_fullStr | Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX |
| title_full_unstemmed | Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX |
| title_short | Matriptase activation of Gq drives epithelial disruption and inflammation via RSK and DUOX |
| title_sort | matriptase activation of gq drives epithelial disruption and inflammation via rsk and duox |
| topic | Science::Medicine Epidermis Epithelia |
| url | https://hdl.handle.net/10356/159382 |
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