Inhibition of Th17 by targeted degradation of HIF1-α

Abstract

Abstract Death-associated protein kinase (DAPK) is a tumor suppressor, while hypoxia-inducible factor 1α (HIF-1α) promotes tumorigenesis in various type of cancers. Here we report a targeted degradation of HIF-1α mediated by DAPK in T helper 17 (Th17) cells. HIF-1α is a transcription factor critical for Th17 development. We found that DAPK inhibits Th17 differentiation and prevents Th17-mediated autoimmune diseases. DAPK suppresses the expression of RORγt and IL-17, which could be attributed to a specific suppression of HIF-1α. In contrast, Th1 cell differentiation and T-bet expression is not affected by DAPK. We demonstrate that DAPK specifically downregulates HIF-1α in a unique process. While HIF-1α is predominant nuclear localized in many cancer cells, HIF-1α is located in both cytosol and nucleus in T cells. This leads to an interaction between HIF-1α and DAPK in T cell cytoplasm. The simultaneous binding of DAPK to prolyl hydroxylase domain protein 2 (PHD2) increases the association between HIF-1α and PHD2. Consequently, DAPK enhances the proline hydroxylation and proteasome degradation of HIF-1α in Th17 cells. DAPK-deficiency thus results in excess HIF-1α accumulation, enhanced Th17 generation, and exacerbated experimental autoimmune encephalomyelitis (EAE). Transgenic DAPK expression, in contrast, suppresses Th17 differentiation and prevents EAE generation. The overproduction of Th17 cells and exacerbated EAE development in Dapk−/− mice is fully reversed by knockout of HIF-1α. Our results demonstrate a new process involving DAPK-mediated degradation of cytoplasmic HIF-1α, and suggest that a potential therapy for Th17-associated inflammatory diseases by targeted elevation of DAPK.