Conditions of endoplasmic reticulum (ER) stress reduce protein synthesis by provoking translation regulation, governed by the eIF2α kinase PERK. When PERK is inhibited during ER stress, retention of a selective subset of glycoproteins occurs, a phenomenon we termed selective ER retention (sERr). sERr clients are enriched with tyrosine kinase receptors (RTKs), which form large molecular weight disulfide bonded complexes in the ER. The protein disulfide isomerase ERp44 promotes sERr and increases the size of sERr complexes. Here we show that sERr is reversible upon washout. Pulse chase analyses show that upon recovery, only a small fraction of the sERr complexes disintegrates and contributes to the matured proteins, while most are newly synthesized. Sequential inductions of sERr and washouts demonstrate an accelerated recovery that is dependent on the unfolded protein response transducer IRE1. Since IRE1 regulates the expression level PDIA6, we analyzed its contribution to sERr. We found that PDIA6 and ERp44 constitutively interact by disulfides and have opposite effects on resumed recovery of trafficking following removal of sERr conditions. Deletion of ERp44 accelerates, while deletion of PDIA6 slows down recovery with a minimal effect on total protein synthesis. ERp44 is a primary interactor with sERr clients. When missing, PDIA6 partitions more into sERr complexes. Deletion of the tumor suppressor PTEN, which induces RTK signaling, promoted sERr formation kinetics, and accelerated the recovery, suggesting feedback between RTKs signaling and sERr. This study suggests that sERr, should develop physiologically or pathologically, is counteracted by adaptation responses that involve IRE1 and PDIA6.

中文翻译：

---

在 ERp44 和 PDIA6 对压力下内质网保留的相反调节。


内质网 （ER） 应激的条件通过激发翻译调节来减少蛋白质合成，翻译调节由 eIF2α 激酶 PERK 控制。当 PERK 在 ER 应激期间受到抑制时，会发生糖蛋白的选择性子集的保留，这种现象我们称为选择性 ER 保留 （sERr）。sERr 客户富含酪氨酸激酶受体 （RTK），这些受体在 ER 中形成大分子量的二硫键复合物。蛋白二硫键异构酶 ERp44 促进 sERr 并增加 sERr 复合物的大小。在这里，我们表明 sERr 在冲洗时是可逆的。脉冲追踪分析表明，在恢复后，只有一小部分 sERr 复合物分解并有助于成熟的蛋白质，而大多数是新合成的。sERr 和清除的连续诱导表明加速恢复，这取决于未折叠的蛋白质反应转导 IRE1。由于 IRE1 调节表达水平 PDIA6，我们分析了其对 sERr 的贡献。我们发现 PDIA6 和 ERp44 通过二硫键组成性相互作用，并且对去除 sERr 条件后恢复贩运具有相反的影响。ERp44 的缺失会加速，而 PDIA6 的缺失会减慢恢复速度，对总蛋白合成的影响最小。ERp44 是与 sERr 客户端的主要交互器。缺失时，PDIA6 会更多地划分为 sERr 复合体。诱导 RTK 信号传导的肿瘤抑制因子 PTEN 的缺失促进了 sERr 形成动力学，并加速了恢复，表明 RTKs 信号传导和 sERr 之间存在反馈。这项研究表明，sERr 应该在生理或病理上发展，被涉及 IRE1 和 PDIA6 的适应反应所抵消。