Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress
Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress
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磷酸化可改变蛋白质二硫键异构酶活性以维持蛋白质稳态并减轻内质网应激
DOI：
10.15252/embj.2019103841
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发表时间：
2020-05-18
期刊：
影响因子：
11.4
通讯作者：
VVang, Lei
中科院分区：
文献类型：
--
作者：
Yu, Jiaojiao;Li, Tao;VVang, Lei
内质网 (ER) 中积累的未折叠蛋白会触发未折叠蛋白反应 (UPR)，从而增加 ER 蛋白折叠能力。内质网蛋白质稳态和 UPR 信号传导需要以精确和及时的方式进行调节。在这里，我们将蛋白质二硫键异构酶（PDI）的磷酸化确定为内质网应激期间的早期事件，蛋白质二硫键异构酶（PDI）是内质网中最丰富和最关键的折叠催化剂之一。分泌途径激酶 Fam20C 磷酸化 PDI 的 Ser357，并对各种 ER 应激源做出快速反应。 Ser357 的磷酸化会诱导 PDI 形成开放构象，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 PDI 还与 IRE1 α（一种主要的 UPR 信号转导器）的管腔结构域结合，并减弱过度的 IRE1 α 活性。重要的是，PDI-S359A 敲入小鼠在急性 ER 应激下表现出增强的 IRE1 α 激活和肝损伤。我们得出的结论是，Fam20C-PDI 轴构成了维持 ER 蛋白质稳态的翻译后反应，并在防止 ER 应激诱导的细胞死亡中发挥着至关重要的作用。
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 IRE1 alpha, a major UPR signal transducer, and attenuates excessive IRE1 alpha activity. Importantly, PDI-S359A knock-in mice display enhanced IRE1 alpha 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.