DGKζ depletion attenuates HIF-1α induction and SIRT1 expression, but enhances TAK1-mediated AMPKα phosphorylation under hypoxia
DGKζ depletion attenuates HIF-1α induction and SIRT1 expression, but enhances TAK1-mediated AMPKα phosphorylation under hypoxia
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DOI：
10.1016/j.cellsig.2020.109618
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发表时间：
2020-07-01
影响因子：
4.8
通讯作者：
Goto, Kaoru
中科院分区：
文献类型：
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作者：
Akimoto, Ryo;Tanaka, Toshiaki;Goto, Kaoru
细胞通过各种机制科普环境变化。涉及HIF-1、SIRT 1和AMPK的通路在应激条件下的能量稳态中起主要作用。二酰基甘油激酶（DGK）构成催化二酰基甘油转化为磷脂酸的酶家族。我们先前报道过，能量消耗如缺血诱导细胞死亡前DGKzeta的蛋白酶体降解，表明DGKzeta参与能量稳态。本研究探讨了DGK zeta缺失如何影响HIF-1 α、SIRT 1和AMPK α的调节。在缺氧条件下，DGK zeta缺失减弱了HIF-1 α诱导和SIRT 1表达，这可能使细胞对能量应激敏感。然而，DGKzeta缺失引起上游激酶TAK 1增强AMPK α磷酸化和细胞内ATP水平增加。结果表明，DGKzeta发挥抑制作用的TAK 1活性的AMPK激活机制，和DGKzeta耗竭可能会导致AMPK介导的能量传感器系统的失调。
Cells cope with environmental changes through various mechanisms. Pathways involving HIF-1, SIRT1, and AMPK play major roles in energy homeostasis under stress conditions. Diacylglycerol kinase (DGK) constitutes an enzyme family that catalyzes conversion of diacylglycerol to phosphatidic acid. We reported earlier that energy depletion such as ischemia induces proteasomal degradation of DGK zeta before cell death, suggesting involvement of DGK zeta in energy homeostasis. This study examines how DGK zeta depletion affects the regulation of HIF-1 alpha, SIRT1, and AMPK alpha. Under hypoxia DGK zeta depletion attenuates HIF-1 alpha induction and SIRT1 expression, which might render cells vulnerable to energy stress. However, DGK zeta depletion engenders enhanced AMPK alpha phosphorylation by upstream kinase TAK1 and an increase in intracellular ATP levels. Results suggest that DGK zeta exerts a suppressive effect on TAK1 activity in the AMPK activation mechanism, and that DGK zeta depletion might engender dysregulation of the AMPK-mediated energy sensor system.