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钙耗竭通过破坏 BiP 底物复合物来挑战内质网的蛋白质稳态。

Calcium depletion challenges endoplasmic reticulum proteostasis by destabilising BiP-substrate complexes.

机构信息

Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.

出版信息

Elife. 2020 Dec 9;9:e62601. doi: 10.7554/eLife.62601.

DOI:10.7554/eLife.62601
PMID:33295873
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7758071/
Abstract

The metazoan endoplasmic reticulum (ER) serves both as a hub for maturation of secreted proteins and as an intracellular calcium storage compartment, facilitating calcium-release-dependent cellular processes. ER calcium depletion robustly activates the unfolded protein response (UPR). However, it is unclear how fluctuations in ER calcium impact organellar proteostasis. Here, we report that calcium selectively affects the dynamics of the abundant metazoan ER Hsp70 chaperone BiP, by enhancing its affinity for ADP. In the calcium-replete ER, ADP rebinding to post-ATP hydrolysis BiP-substrate complexes competes with ATP binding during both spontaneous and co-chaperone-assisted nucleotide exchange, favouring substrate retention. Conversely, in the calcium-depleted ER, relative acceleration of ADP-to-ATP exchange favours substrate release. These findings explain the rapid dissociation of certain substrates from BiP observed in the calcium-depleted ER and suggest a mechanism for tuning ER quality control and coupling UPR activity to signals that mobilise ER calcium in secretory cells.

摘要

真核生物内质网 (ER) 既是分泌蛋白成熟的枢纽，也是细胞内钙储存室，有助于钙释放依赖的细胞过程。内质网钙耗竭强烈激活未折叠蛋白反应 (UPR)。然而，内质网钙波动如何影响细胞器蛋白质稳态尚不清楚。在这里，我们报告钙通过增强其与 ADP 的亲和力，选择性地影响丰富的真核生物 ER Hsp70 伴侣 BiP 的动态。在钙充足的 ER 中，ADP 与 ATP 水解后 BiP-底物复合物的再结合在自发和共伴侣辅助核苷酸交换过程中与 ATP 结合竞争，有利于底物保留。相反，在钙耗竭的 ER 中，ADP 到 ATP 交换的相对加速有利于底物释放。这些发现解释了在钙耗竭的 ER 中观察到的某些底物与 BiP 的快速解离，并为调节 ER 质量控制和将 UPR 活性与动员分泌细胞内质网钙的信号耦合提供了一种机制。

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