A virtuous cycle operated by ERp44 and ERGIC-53 guarantees proteostasis in the early secretory compartment

The composition of the secretome depends on the combined action of cargo receptors that facilitate protein transport and sequential checkpoints that restrict it to native conformers. Acting after endoplasmic reticulum (ER)-resident chaperones, ERp44 retrieves its clients from downstream compartments. To guarantee efficient quality control, ERp44 should exit the ER as rapidly as its clients, or more. Here, we show that appending ERp44 to different cargo proteins increases their secretion rates. ERp44 binds the cargo receptor ER-Golgi intermediate compartment (ERGIC)-53 in the ER to negotiate preferential loading into COPII vesicles. Silencing ERGIC-53, or competing for its COPII binding with 4-phenylbutyrate, causes secretion of Prdx4, an enzyme that relies on ERp44 for intracellular localization. In more acidic, zinc-rich downstream compartments, ERGIC-53 releases its clients and ERp44, which can bind and retrieve non-native conformers via KDEL receptors. By coupling the transport of cargoes and inspector proteins, cells ensure efficiency and fidelity of secretion.
DOI: 10.1016/j.isci.2021.102244

分泌组（secretome）的组成由两类分子的协同作用共同调控：一类是介导蛋白质转运的货物受体，另一类是限定分泌组仅保留天然构象的顺次检查点。在内质网（ER）驻留分子伴侣发挥作用后，ERp44可从下游区域回收其靶蛋白。为保障高效的分泌质量控制，ERp44需与其靶蛋白同步，甚至更快速地从内质网中输出。本研究证实，将ERp44与不同货物蛋白融合可提升后者的分泌速率。ERp44在内质网中结合货物受体ER-高尔基体中间室（ER-Golgi intermediate compartment, ERGIC）-53，从而实现优先被装载进入COPII囊泡（COPII vesicles）。沉默ERGIC-53基因，或通过4-苯基丁酸（4-phenylbutyrate）竞争其COPII结合位点，会导致依赖ERp44实现胞内定位的过氧化物还原酶4（Prdx4）发生异常分泌。在酸性更强、锌离子富集的下游区域中，ERGIC-53会释放其结合的靶蛋白与ERp44；ERp44可通过KDEL受体（KDEL receptors）结合并回收非天然构象的蛋白质。通过将货物蛋白与监察蛋白的转运过程偶联，细胞可确保分泌过程的高效性与保真度。
DOI: 10.1016/j.isci.2021.102244