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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Death-Associated Protein Kinases / deficiency
-
Death-Associated Protein Kinases / genetics*
-
Death-Associated Protein Kinases / immunology
-
Encephalomyelitis, Autoimmune, Experimental / genetics*
-
Encephalomyelitis, Autoimmune, Experimental / immunology
-
Encephalomyelitis, Autoimmune, Experimental / pathology
-
Gene Expression Regulation
-
HEK293 Cells
-
HeLa Cells
-
Humans
-
Hydroxylation
-
Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
-
Hypoxia-Inducible Factor 1, alpha Subunit / immunology
-
Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors
-
Hypoxia-Inducible Factor-Proline Dioxygenases / genetics*
-
Hypoxia-Inducible Factor-Proline Dioxygenases / immunology
-
Interleukin-17 / genetics
-
Interleukin-17 / immunology
-
Jurkat Cells
-
Mice
-
Mice, Knockout
-
Myelin-Oligodendrocyte Glycoprotein / administration & dosage
-
Peptide Fragments / administration & dosage
-
Pertussis Toxin / administration & dosage
-
Proline / metabolism
-
Proteasome Endopeptidase Complex
-
Proteolysis
-
RNA, Small Interfering / genetics
-
RNA, Small Interfering / metabolism
-
Signal Transduction
-
T-Lymphocytes, Regulatory / drug effects
-
T-Lymphocytes, Regulatory / immunology
-
T-Lymphocytes, Regulatory / pathology
-
Th17 Cells / drug effects
-
Th17 Cells / immunology*
-
Th17 Cells / pathology
Substances
-
Hif1a protein, mouse
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
Interleukin-17
-
Myelin-Oligodendrocyte Glycoprotein
-
Peptide Fragments
-
RNA, Small Interfering
-
myelin oligodendrocyte glycoprotein (35-55)
-
Proline
-
Egln1 protein, mouse
-
Hypoxia-Inducible Factor-Proline Dioxygenases
-
Pertussis Toxin
-
Dapk1 protein, mouse
-
Death-Associated Protein Kinases
-
Proteasome Endopeptidase Complex