Cargando…
Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression
Death-associated protein kinase (DAPK) is a tumour suppressor. Here we show that DAPK also inhibits T helper 17 (Th17) and prevents Th17-mediated pathology in a mouse model of autoimmunity. We demonstrate that DAPK specifically downregulates hypoxia-inducible factor 1α (HIF-1α). In contrast to the p...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915028/ https://www.ncbi.nlm.nih.gov/pubmed/27312851 http://dx.doi.org/10.1038/ncomms11904 |
_version_ | 1782438631077576704 |
---|---|
author | Chou, Ting-Fang Chuang, Ya-Ting Hsieh, Wan-Chen Chang, Pei-Yun Liu, Hsin-Yu Mo, Shu-Ting Hsu, Tzu-Sheng Miaw, Shi-Chuen Chen, Ruey-Hwa Kimchi, Adi Lai, Ming-Zong |
author_facet | Chou, Ting-Fang Chuang, Ya-Ting Hsieh, Wan-Chen Chang, Pei-Yun Liu, Hsin-Yu Mo, Shu-Ting Hsu, Tzu-Sheng Miaw, Shi-Chuen Chen, Ruey-Hwa Kimchi, Adi Lai, Ming-Zong |
author_sort | Chou, Ting-Fang |
collection | PubMed |
description | Death-associated protein kinase (DAPK) is a tumour suppressor. Here we show that DAPK also inhibits T helper 17 (Th17) and prevents Th17-mediated pathology in a mouse model of autoimmunity. We demonstrate that DAPK specifically downregulates hypoxia-inducible factor 1α (HIF-1α). In contrast to the predominant nuclear localization of HIF-1α in many cell types, HIF-1α is located in both the cytoplasm and nucleus in T cells, allowing for a cytosolic DAPK–HIF-1α interaction. DAPK also binds prolyl hydroxylase domain protein 2 (PHD2) and increases HIF-1α-PHD2 association. DAPK thereby promotes the proline hydroxylation and proteasome degradation of HIF-1α. Consequently, DAPK deficiency leads to excess HIF-1α accumulation, enhanced IL-17 expression and exacerbated experimental autoimmune encephalomyelitis. Additional knockout of HIF-1α restores the normal differentiation of Dapk(−/−) Th17 cells and prevents experimental autoimmune encephalomyelitis development. Our results reveal a mechanism involving DAPK-mediated degradation of cytoplasmic HIF-1α, and suggest that raising DAPK levels could be used for treatment of Th17-associated inflammatory diseases. |
format | Online Article Text |
id | pubmed-4915028 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49150282016-06-29 Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression Chou, Ting-Fang Chuang, Ya-Ting Hsieh, Wan-Chen Chang, Pei-Yun Liu, Hsin-Yu Mo, Shu-Ting Hsu, Tzu-Sheng Miaw, Shi-Chuen Chen, Ruey-Hwa Kimchi, Adi Lai, Ming-Zong Nat Commun Article Death-associated protein kinase (DAPK) is a tumour suppressor. Here we show that DAPK also inhibits T helper 17 (Th17) and prevents Th17-mediated pathology in a mouse model of autoimmunity. We demonstrate that DAPK specifically downregulates hypoxia-inducible factor 1α (HIF-1α). In contrast to the predominant nuclear localization of HIF-1α in many cell types, HIF-1α is located in both the cytoplasm and nucleus in T cells, allowing for a cytosolic DAPK–HIF-1α interaction. DAPK also binds prolyl hydroxylase domain protein 2 (PHD2) and increases HIF-1α-PHD2 association. DAPK thereby promotes the proline hydroxylation and proteasome degradation of HIF-1α. Consequently, DAPK deficiency leads to excess HIF-1α accumulation, enhanced IL-17 expression and exacerbated experimental autoimmune encephalomyelitis. Additional knockout of HIF-1α restores the normal differentiation of Dapk(−/−) Th17 cells and prevents experimental autoimmune encephalomyelitis development. Our results reveal a mechanism involving DAPK-mediated degradation of cytoplasmic HIF-1α, and suggest that raising DAPK levels could be used for treatment of Th17-associated inflammatory diseases. Nature Publishing Group 2016-06-17 /pmc/articles/PMC4915028/ /pubmed/27312851 http://dx.doi.org/10.1038/ncomms11904 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Chou, Ting-Fang Chuang, Ya-Ting Hsieh, Wan-Chen Chang, Pei-Yun Liu, Hsin-Yu Mo, Shu-Ting Hsu, Tzu-Sheng Miaw, Shi-Chuen Chen, Ruey-Hwa Kimchi, Adi Lai, Ming-Zong Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression |
title | Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression |
title_full | Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression |
title_fullStr | Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression |
title_full_unstemmed | Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression |
title_short | Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression |
title_sort | tumour suppressor death-associated protein kinase targets cytoplasmic hif-1α for th17 suppression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915028/ https://www.ncbi.nlm.nih.gov/pubmed/27312851 http://dx.doi.org/10.1038/ncomms11904 |
work_keys_str_mv | AT choutingfang tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression AT chuangyating tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression AT hsiehwanchen tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression AT changpeiyun tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression AT liuhsinyu tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression AT moshuting tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression AT hsutzusheng tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression AT miawshichuen tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression AT chenrueyhwa tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression AT kimchiadi tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression AT laimingzong tumoursuppressordeathassociatedproteinkinasetargetscytoplasmichif1aforth17suppression |