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.
Highlights
Death-associated protein kinase (DAPK) is a tumour suppressor
IFN-g production was similar between WT and Dapk À / À T cells when cultured in Th0 conditions (Supplementary Fig. 2d)
We further found that the levels of RORgt and RORa—the transcription factors dictating IL-17 expression—were elevated in DAPK-deficient T helper 17 (Th17) cells; even though activation of the Rorc inducer STAT3 was similar between WT and Dapk À / À T cells (Fig. 2i; Supplementary Fig. 5g)
Summary
Death-associated protein kinase (DAPK) is a tumour suppressor. Here we show that DAPK inhibits T helper 17 (Th17) and prevents Th17-mediated pathology in a mouse model of autoimmunity. Additional knockout of HIF-1a restores the normal differentiation of Dapk À / À Th17 cells and prevents experimental autoimmune encephalomyelitis development. The T helper 17 (Th17) subset of immune cells plays critical roles in modulating tissue inflammation and combating microbial infections Due to their inflammatory nature, Th17 cells contribute to autoimmune diseases[1,2,3]. Hypoxia-inducible factor-1a (HIF-1a) is an oxygen tension sensor widely expressed in different cell types, including Th17 cells. HIF-1a is highly expressed in Th17 cells[26,27], priming at physiological oxygen tension in the presence of inflammatory cytokines. HIF-1a plays a prominent role in Th17 cell differentiation[26,27] by activating the transcription of Rorc (RORgt), and it helps recruit CBP/p300 to the RORgt transcription complex but does not directly bind to the IL-17 promoter[27]. HIF-1a is essential for oxygen homoeostasis, and curtailment of the protective effects of HIF-1a by HIF-1a inhibitors may limit their application
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