| First Author | Chou TF | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 11904 | PubMed ID | 27312851 |
| Mgi Jnum | J:239885 | Mgi Id | MGI:5881989 |
| Doi | 10.1038/ncomms11904 | Citation | Chou TF, et al. (2016) Tumour suppressor death-associated protein kinase targets cytoplasmic HIF-1alpha for Th17 suppression. Nat Commun 7:11904 |
| abstractText | 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 1alpha (HIF-1alpha). In contrast to the predominant nuclear localization of HIF-1alpha in many cell types, HIF-1alpha is located in both the cytoplasm and nucleus in T cells, allowing for a cytosolic DAPK-HIF-1alpha interaction. DAPK also binds prolyl hydroxylase domain protein 2 (PHD2) and increases HIF-1alpha-PHD2 association. DAPK thereby promotes the proline hydroxylation and proteasome degradation of HIF-1alpha. Consequently, DAPK deficiency leads to excess HIF-1alpha accumulation, enhanced IL-17 expression and exacerbated experimental autoimmune encephalomyelitis. Additional knockout of HIF-1alpha 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-1alpha, and suggest that raising DAPK levels could be used for treatment of Th17-associated inflammatory diseases. |
