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 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.
Graduate Institute of Life Sciences, National Defense Medical College, Taipei 11490, Taiwan.|Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Ting-Fang
TF
Chou
Department of Medical Research, National Taiwan University Hospital, Taipei 10002, Taiwan.
Ya-Ting
YT
Chuang
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Wan-Chen
WC
Hsieh
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Pei-Yun
PY
Chang
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Hsin-Yu
HY
Liu
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Shu-Ting
ST
Mo
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
Tzu-Sheng
TS
Hsu
Institute of Immunology, National Taiwan University, Taipei 10057, Taiwan.
Shi-Chuen
SC
Miaw
Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.|Institute of Molecular Medicine, National Taiwan University, Taipei 10057, Taiwan.
Ruey-Hwa
RH
Chen
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Adi
A
Kimchi
Graduate Institute of Life Sciences, National Defense Medical College, Taipei 11490, Taiwan.|Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.|Institute of Immunology, National Taiwan University, Taipei 10057, Taiwan.
Ming-Zong
0000-0002-3237-4803
MZ
Lai
D000818:Animals; D064550:Death-Associated Protein Kinases / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000276:immunology; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000008:administration & dosage; D010446:Peptide Fragments / Q000008:administration & dosage; D037342:Pertussis Toxin / Q000008:administration & dosage; D011392:Proline / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C445081:myelin oligodendrocyte glycoprotein (35-55); D011392:Proline; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D037342:Pertussis Toxin; C579106:Dapk1 protein, mouse; D064550:Death-Associated Protein Kinases; D046988:Proteasome Endopeptidase Complex