Chou, Ting-FangTing-FangChouChuang, Ya-TingYa-TingChuangHsieh, Wan-ChenWan-ChenHsiehChang, Pei-YunPei-YunChangLiu, Hsin-YuHsin-YuLiuMo, Shu-TingShu-TingMoHsu, Tzu-ShengTzu-ShengHsuSHI-CHUEN MIAWChen, Ruey-HwaRuey-HwaChenKimchi, AdiAdiKimchiLai, Ming-ZongMing-ZongLai2019-08-062019-08-0620162041-1723https://www.scopus.com/inward/record.uri?eid=2-s2.0-84975516240&doi=10.1038%2fncomms11904&partnerID=40&md5=455e5859d18aaa336bb9f3b3b30c6d00https://scholars.lib.ntu.edu.tw/handle/123456789/416283Death-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.en[SDGs]SDG3death 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 Cellsjournal article10.1038/ncomms11904273128512-s2.0-84975516240WOS:000379080400001https://api.elsevier.com/content/abstract/scopus_id/84975516240