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

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 1? (HIF-1?). In contrast to the predominant nuclear localization of HIF-1? in many cell types, HIF-1? is located in both the cytoplasm and nucleus in T cells, allowing for a cytosolic DAPK-HIF-1? interaction. DAPK also binds prolyl hydroxylase domain protein 2 (PHD2) and increases HIF-1?-PHD2 association. DAPK thereby promotes the proline hydroxylation and proteasome degradation of HIF-1?. Consequently, DAPK deficiency leads to excess HIF-1? accumulation, enhanced IL-17 expression and exacerbated experimental autoimmune encephalomyelitis. Additional knockout of HIF-1? 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-1?, and suggest that raising DAPK levels could be used for treatment of Th17-associated inflammatory diseases.

SUBMITTER: Chou TF 

PROVIDER: S-EPMC4915028 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature