Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress-induced autophagy
Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress-induced autophagy
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DOI：
10.15252/embr.201642565
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发表时间：
2016-11-01
期刊：
影响因子：
7.7
通讯作者：
Shimizu, Shigeomi
中科院分区：
文献类型：
--
作者：
Torii, Satoru;Yoshida, Tatsushi;Shimizu, Shigeomi
自噬是一个进化保守的过程，降解亚细胞成分。与饥饿诱导的自噬不同，基因毒性应激诱导的自噬的分子机制尚未完全阐明。在这项研究中，我们分析了基因毒性应激诱导自噬的分子机制，并确定了蛋白磷酸酶1D镁依赖性δ异构体（PPM1D）催化的un51样激酶1 (Ulk1) Ser（637）的去磷酸化的重要作用。我们发现暴露于基因毒性应激后，PPM1D以p53依赖的方式与Ulk1的Ser（637）相互作用并使其去磷酸化。ppm1d依赖的Ulk1去磷酸化触发Ulk1斑点形成并诱导自噬。这不仅发生在小鼠胚胎成纤维细胞中，也发生在原代胸腺细胞中，其中PPM1D的遗传消融减少了Ulk1 Ser（637）的去磷酸化，抑制自噬，并加速x射线照射诱导的细胞凋亡。细胞凋亡的加速主要是由于自噬机制无法降解促凋亡分子Noxa。这些发现表明PPM1D-Ulk1轴在基因毒性应激诱导的自噬中起关键作用。
Autophagy is an evolutionary conserved process that degrades subcellular constituents. Unlike starvation-induced autophagy, the molecular mechanism of genotoxic stress-induced autophagy has not yet been fully elucidated. In this study, we analyze the molecular mechanism of genotoxic stress-induced autophagy and identify an essential role of dephosphorylation of the Unc51-like kinase 1 (Ulk1) at Ser(637), which is catalyzed by the protein phosphatase 1D magnesium-dependent delta isoform (PPM1D). We show that after exposure to genotoxic stress, PPM1D interacts with and dephosphorylates Ulk1 at Ser(637) in a p53-dependent manner. The PPM1D-dependent Ulk1 dephosphorylation triggers Ulk1 puncta formation and induces autophagy. This happens not only in mouse embryonic fibroblasts but also in primary thymocytes, where the genetic ablation of PPM1D reduces the dephosphorylation of Ulk1 at Ser(637), inhibits autophagy, and accelerates apoptosis induced by X-ray irradiation. This acceleration of apoptosis is caused mainly by the inability of the autophagic machinery to degrade the proapoptotic molecule Noxa. These findings indicate that the PPM1D-Ulk1 axis plays a pivotal role in genotoxic stress-induced autophagy.