Leder Anna, Mas Guillaume, Szentgyörgyi Viktória, Jakob Roman P, Maier Timm, Spang Anne, Hiller Sebastian
Biozentrum, University of Basel, Basel, Switzerland.
Nat Cell Biol. 2025 Aug 11. doi: 10.1038/s41556-025-01730-w.
Protein folding in the endoplasmic reticulum (ER) relies on a network of molecular chaperones that facilitates the folding and maturation of client proteins. How the ER chaperones organize in a supramolecular manner to exert their cooperativity has, however, remained unclear. Here we report the discovery of a multichaperone condensate in the ER lumen, which is formed around the chaperone PDIA6 during protein folding homeostasis. The condensates form in a Ca-dependent manner and we resolve the underlying mechanism at the atomic and cellular levels. The PDIA6 condensates recruit further chaperones-Hsp70 BiP, J-domain protein ERdj3, disulfide isomerase PDIA1 and Hsp90 Grp94-which constitute some of the essential components of the early folding machinery. The chaperone condensates enhance folding of proteins, such as proinsulin, and prevent protein misfolding in the ER lumen. The PDIA6-scaffolded chaperone condensates hence provide the functional basis for spatial and temporal coordination of the dynamic ER chaperone network.
内质网（ER）中的蛋白质折叠依赖于一个分子伴侣网络，该网络促进客户蛋白的折叠和成熟。然而，内质网分子伴侣如何以超分子方式组织以发挥其协同作用仍不清楚。在这里，我们报告在内质网腔中发现了一种多分子伴侣凝聚物，它在蛋白质折叠稳态期间围绕分子伴侣PDIA6形成。凝聚物以钙依赖的方式形成，我们在原子和细胞水平上解析了其潜在机制。PDIA6凝聚物招募了更多的分子伴侣——热休克蛋白70（Hsp70）BiP、J结构域蛋白ERdj3、二硫键异构酶PDIA1和热休克蛋白90（Hsp90）Grp94——它们构成了早期折叠机制的一些重要组成部分。分子伴侣凝聚物增强了诸如胰岛素原等蛋白质的折叠，并防止内质网腔内蛋白质错误折叠。因此，以PDIA6为支架的分子伴侣凝聚物为动态内质网分子伴侣网络的时空协调提供了功能基础。
