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

Ting-Fang Chou, Ya-Ting Chuang, Wan-Chen Hsieh, Pei-Yun Chang, Hsin-Yu Liu, Shu-Ting Mo, Tzu-Sheng Hsu, Shi-Chuen Miaw, Ruey-Hwa Chen, Adi Kimchi and Ming-Zong Lai ()
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Ting-Fang Chou: Graduate Institute of Life Sciences, National Defense Medical College
Ya-Ting Chuang: National Taiwan University Hospital
Wan-Chen Hsieh: Institute of Molecular Biology, Academia Sinica
Pei-Yun Chang: Institute of Molecular Biology, Academia Sinica
Hsin-Yu Liu: Institute of Molecular Biology, Academia Sinica
Shu-Ting Mo: Institute of Molecular Biology, Academia Sinica
Tzu-Sheng Hsu: Institute of Molecular Biology, Academia Sinica
Shi-Chuen Miaw: Institute of Immunology, National Taiwan University
Ruey-Hwa Chen: Institute of Biological Chemistry, Academia Sinica
Adi Kimchi: Weizmann Institute of Science
Ming-Zong Lai: Graduate Institute of Life Sciences, National Defense Medical College

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11904

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