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

Chou, TF;Chuang, YT;Hsieh, WC;Chang, PY;Liu, HY;Mo, ST;Hsu, TS;Miaw, SC;Chen, RH;Kimchi, A;Lai, MZ;

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.