ATM-associated signalling triggers the unfolded protein response and cell death in response to stress
ATM-associated signalling triggers the unfolded protein response and cell death in response to stress
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DOI：
10.1038/s42003-020-1102-2
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发表时间：
2020-07-14
影响因子：
5.9
通讯作者：
Nakamura，Takashi
中科院分区：
文献类型：
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作者：
Hotokezaka，Yuka;Katayama，Ikuo;Nakamura，Takashi
内质网 (ER) 应激可能是由于内质网腔内未折叠/错误折叠蛋白质的积累导致内质网功能扰动引起的。积累的未折叠蛋白通过激活 ER 上的三个跨膜传感器（IRE1α、PERK 和 ATF6）来触发未折叠蛋白反应 (UPR)。这些分子的协调作用上调了编码蛋白质的基因，这些蛋白质参与了蛋白质合成的下调和蛋白质分泌的加速。这些故障安全机制的无效可能导致细胞凋亡。然而，UPR上游的分子机制尚不完全清楚。在这里，我们展示了共济失调毛细血管扩张突变（ATM）参与应激诱导的细胞凋亡。细胞质 ATM 作为一个平台，AKT 的蛋白磷酸酶 2A 依赖性去磷酸化激活糖原合酶激酶 3β，从而下调新生多肽相关复合物 α 亚基和 γ-taxilin，触发 UPR 并导致线粒体依赖性细胞凋亡。这些结果表明，各种形式的压力都会触发 ATM/AKT 依赖性细胞死亡途径。
Endoplasmic reticulum (ER) stress can be caused by perturbations in ER function resulting from the accumulation of unfolded/misfolded proteins in the ER lumen. Accumulating unfolded proteins trigger unfolded protein responses (UPRs) through activating three transmembrane sensors on the ER: IRE1α, PERK, and ATF6. The orchestrated action of these molecules upregulates genes encoding proteins involved in the downregulation of protein synthesis and acceleration of protein secretion. Ineffectiveness of these fail-safe mechanisms may lead to apoptosis. However, the molecular mechanisms upstream of the UPR are not fully understood. Here we show participation of ataxia telangiectasia mutated (ATM) in stress-induced apoptosis. Cytoplasmic ATM serves as a platform on which protein phosphatase 2A-dependent dephosphorylation of AKT activates glycogen synthase kinase 3β, thereby downregulating nascent polypeptide-associated complex α subunit and γ-taxilin, triggering UPRs and leading to mitochondria-dependent apoptosis. These results suggest an ATM/AKT-dependent cell death pathway triggered by various forms of stress.