The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria
The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria
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DOI：
10.1016/j.celrep.2022.111899
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发表时间：
2023-01-31
期刊：
影响因子：
8.8
通讯作者：
Simmen, Thomas
中科院分区：
文献类型：
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作者：
Bassot, Arthur;Chen, Junsheng;Simmen, Thomas
内质网(ER)的动态平衡需要分子调节剂，使线粒体生物能量学适应蛋白质折叠的需要。例如，Calnexin通过NADPH氧化酶4(NOX4)产生的活性氧(ROS)维持线粒体新陈代谢和线粒体-内质网接触(MERS)。然而，内质网应激的诱导需要线粒体快速的分子重新布线来适应新的能量需求。这台机器没有特点。我们现在证明，氧化还原酶ERO1a在衣霉素处理后与蛋白激酶RNA样ER激酶(PERK)发生共价相互作用。PERK-ERO1a相互作用需要ERO1a的C端活性部位和PERK的半胱氨酸216。此外，我们还表明，perk-ERO1a复合体促进了Merc蛋白的氧化，并控制了线粒体的动力学。使用蛋白质探针，我们确定这些功能改善了内质网-线粒体钙离子通量，以维持两个器官细胞中的生物能量，同时限制氧化应激。因此，PERK-ERO1a复合体是一种关键的分子机制，允许快速代谢适应内质网应激。
Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria -ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induc-tion of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1a covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1a interaction requires the C-terminal active site of ERO1a and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1a complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca2+ flux to maintain bioenergetics in both organ-elles, while limiting oxidative stress. Therefore, the PERK-ERO1a complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.