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Exocyst inactivation in urothelial cells disrupts autophagy and activates non-canonical NF-κB signaling
Ureter obstruction is a highly prevalent event during embryonic development and is a major cause of pediatric kidney disease. We have previously reported that ureteric bud-specific ablation of the gene expressing the exocyst subunit EXOC5 in late murine gestation results in failure of urothelial str...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Company of Biologists Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9586569/ https://www.ncbi.nlm.nih.gov/pubmed/36004645 http://dx.doi.org/10.1242/dmm.049785 |
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author | Ortega, Michael A. Villiger, Ross K. Harrison-Chau, Malia Lieu, Suzanna Tamashiro, Kadee-Kalia Lee, Amanda J. Fujimoto, Brent A. Patwardhan, Geetika Y. Kepler, Joshua Fogelgren, Ben |
author_facet | Ortega, Michael A. Villiger, Ross K. Harrison-Chau, Malia Lieu, Suzanna Tamashiro, Kadee-Kalia Lee, Amanda J. Fujimoto, Brent A. Patwardhan, Geetika Y. Kepler, Joshua Fogelgren, Ben |
author_sort | Ortega, Michael A. |
collection | PubMed |
description | Ureter obstruction is a highly prevalent event during embryonic development and is a major cause of pediatric kidney disease. We have previously reported that ureteric bud-specific ablation of the gene expressing the exocyst subunit EXOC5 in late murine gestation results in failure of urothelial stratification, cell death and complete ureter obstruction. However, the mechanistic connection between disrupted exocyst activity, urothelial cell death and subsequent ureter obstruction was unclear. Here, we report that inhibited urothelial stratification does not drive cell death during ureter development. Instead, we demonstrate that the exocyst plays a critical role in autophagy in urothelial cells, and that disruption of autophagy activates a urothelial NF-κB stress response. Impaired autophagy first provokes canonical NF-κB activity, which is progressively followed by increasing levels of non-canonical NF-κB activity and cell death if the stress remains unresolved. Furthermore, we demonstrate that ureter obstructions can be completely rescued in Exoc5 conditional knockout mice by administering a single dose of the pan-caspase inhibitor z-VAD-FMK at embryonic day 16.5 prior to urothelial cell death. Taken together, ablation of Exoc5 disrupts autophagic stress response and activates progressive NF-κB signaling, which promotes obstructive uropathy. |
format | Online Article Text |
id | pubmed-9586569 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The Company of Biologists Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-95865692022-10-24 Exocyst inactivation in urothelial cells disrupts autophagy and activates non-canonical NF-κB signaling Ortega, Michael A. Villiger, Ross K. Harrison-Chau, Malia Lieu, Suzanna Tamashiro, Kadee-Kalia Lee, Amanda J. Fujimoto, Brent A. Patwardhan, Geetika Y. Kepler, Joshua Fogelgren, Ben Dis Model Mech Research Article Ureter obstruction is a highly prevalent event during embryonic development and is a major cause of pediatric kidney disease. We have previously reported that ureteric bud-specific ablation of the gene expressing the exocyst subunit EXOC5 in late murine gestation results in failure of urothelial stratification, cell death and complete ureter obstruction. However, the mechanistic connection between disrupted exocyst activity, urothelial cell death and subsequent ureter obstruction was unclear. Here, we report that inhibited urothelial stratification does not drive cell death during ureter development. Instead, we demonstrate that the exocyst plays a critical role in autophagy in urothelial cells, and that disruption of autophagy activates a urothelial NF-κB stress response. Impaired autophagy first provokes canonical NF-κB activity, which is progressively followed by increasing levels of non-canonical NF-κB activity and cell death if the stress remains unresolved. Furthermore, we demonstrate that ureter obstructions can be completely rescued in Exoc5 conditional knockout mice by administering a single dose of the pan-caspase inhibitor z-VAD-FMK at embryonic day 16.5 prior to urothelial cell death. Taken together, ablation of Exoc5 disrupts autophagic stress response and activates progressive NF-κB signaling, which promotes obstructive uropathy. The Company of Biologists Ltd 2022-10-12 /pmc/articles/PMC9586569/ /pubmed/36004645 http://dx.doi.org/10.1242/dmm.049785 Text en © 2022. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | Research Article Ortega, Michael A. Villiger, Ross K. Harrison-Chau, Malia Lieu, Suzanna Tamashiro, Kadee-Kalia Lee, Amanda J. Fujimoto, Brent A. Patwardhan, Geetika Y. Kepler, Joshua Fogelgren, Ben Exocyst inactivation in urothelial cells disrupts autophagy and activates non-canonical NF-κB signaling |
title | Exocyst inactivation in urothelial cells disrupts autophagy and activates non-canonical NF-κB signaling |
title_full | Exocyst inactivation in urothelial cells disrupts autophagy and activates non-canonical NF-κB signaling |
title_fullStr | Exocyst inactivation in urothelial cells disrupts autophagy and activates non-canonical NF-κB signaling |
title_full_unstemmed | Exocyst inactivation in urothelial cells disrupts autophagy and activates non-canonical NF-κB signaling |
title_short | Exocyst inactivation in urothelial cells disrupts autophagy and activates non-canonical NF-κB signaling |
title_sort | exocyst inactivation in urothelial cells disrupts autophagy and activates non-canonical nf-κb signaling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9586569/ https://www.ncbi.nlm.nih.gov/pubmed/36004645 http://dx.doi.org/10.1242/dmm.049785 |
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