Accumulated unfolded proteins in the endoplasmic reticulum (ER) trigger the unfolded protein response (UPR) to increase ER protein folding capacity. ER proteostasis and UPR signaling need to be regulated in a precise and timely manner. Here, we identify phosphorylation of protein disulfide isomerase (PDI), one of the most abundant and critical folding catalysts in the ER, as an early event during ER stress. The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity. Importantly, PDI-S359A knock-in mice display enhanced IRE1α activation and liver damage under acute ER stress. We conclude that the Fam20C-PDI axis constitutes a post-translational response to maintain ER proteostasis and plays a vital role in protecting against ER stress-induced cell death.

中文翻译：

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磷酸化可切换蛋白质二硫键异构酶活性，以维持蛋白稳态并减轻内质网应激。

内质网（ER）中积累的未折叠蛋白会触发未折叠蛋白反应（UPR），以增加ER蛋白折叠能力。ER蛋白质变形和UPR信号传递需要准确，及时地进行调节。在这里，我们确定蛋白二硫键异构酶（PDI）的磷酸化是ER应激中的早期事件，PDI是ER中最丰富和关键的折叠催化剂之一。分泌途径激酶Fam20C使PDI的Ser357磷酸化，并迅速响应各种ER应激源。Ser357的磷酸化诱导了PDI的开放构象，并将其从“折叠酶”转变为“保持酶”，这对于防止ER中的蛋白质错误折叠至关重要。磷酸化的PDI还与主要的UPR信号转导子IRE1α的腔结构域结合，并减弱了过多的IRE1α活性。重要的是，在急性内质网应激下，PDI-S359A敲入小鼠表现出增强的IRE1α活化和肝损伤。我们得出的结论是，Fam20C-PDI轴构成了翻译后反应，以维持内质网蛋白水解，并在防御内质网应激诱导的细胞死亡中起着至关重要的作用。