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  4. Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression
 
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Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1α for Th17 suppression

Journal
Nature communications
Journal Volume
7
Journal Issue
1
Date Issued
2016
Author(s)
Chou, Ting-Fang
Chuang, Ya-Ting
Hsieh, Wan-Chen
Chang, Pei-Yun
Liu, Hsin-Yu
Mo, Shu-Ting
Hsu, Tzu-Sheng
SHI-CHUEN MIAW  
Chen, Ruey-Hwa
Kimchi, Adi
Lai, Ming-Zong
DOI
10.1038/ncomms11904
URI
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84975516240&doi=10.1038%2fncomms11904&partnerID=40&md5=455e5859d18aaa336bb9f3b3b30c6d00
https://scholars.lib.ntu.edu.tw/handle/123456789/416283
URL
https://api.elsevier.com/content/abstract/scopus_id/84975516240
Abstract
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.
SDGs

[SDGs]SDG3

Other Subjects
death associated protein kinase; hypoxia inducible factor 1alpha; interleukin 17; procollagen proline 2 oxoglutarate 4 dioxygenase; proline; proteasome; Dapk1 protein, mouse; death associated protein kinase; Egln1 protein, mouse; Hif1a protein, mouse; hypoxia inducible factor 1alpha; hypoxia inducible factor proline dioxygenase; interleukin 17; myelin oligodendrocyte glycoprotein; myelin oligodendrocyte glycoprotein (35-55); peptide fragment; pertussis toxin; proline; proteasome; small interfering RNA; cytoplasm; degradation; differentiation; disease; enzyme; enzyme activity; pathology; protein; rodent; tumor; animal cell; animal experiment; Article; autoimmunity; cell differentiation; cell nucleus; cells by body anatomy; cellular distribution; controlled study; cytoplasm; down regulation; experimental autoimmune encephalomyelitis; female; hydroxylation; male; mouse; nonhuman; protein binding; protein degradation; protein expression; protein protein interaction; Th17 cell; animal; antagonists and inhibitors; deficiency; drug effect; experimental autoimmune encephalomyelitis; gene expression regulation; genetics; HEK293 cell line; HeLa cell line; human; immunology; Jurkat cell line; knockout mouse; metabolism; pathology; regulatory T lymphocyte; signal transduction; Th17 cell; Animals; Death-Associated Protein Kinases; Encephalomyelitis, Autoimmune, Experimental; Gene Expression Regulation; HEK293 Cells; HeLa Cells; Humans; Hydroxylation; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Interleukin-17; Jurkat Cells; Mice; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Pertussis Toxin; Proline; Proteasome Endopeptidase Complex; Proteolysis; RNA, Small Interfering; Signal Transduction; T-Lymphocytes, Regulatory; Th17 Cells
Publisher
NATURE PUBLISHING GROUP
Type
journal article

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