The endoplasmic reticulum (ER), responsible for processing approximately one-third of the human proteome including most secreted and membrane proteins, plays a pivotal role in protein homeostasis (proteostasis). Dysregulation of ER proteostasis has been implicated in a number of disease states. As such, continued efforts are directed at elucidating mechanisms of ER protein quality control which are mediated by transient and dynamic protein-protein interactions with molecular chaperones, co-chaperones, protein folding and trafficking factors that take place in and around the ER. Technological advances in mass spectrometry have played a pivotal role in characterizing and understanding these protein-protein interactions that dictate protein quality control mechanisms. Here, we highlight the recent progress from mass spectrometry-based investigation of ER protein quality control in revealing the topological arrangement of the proteostasis network, stress response mechanisms that adjust the ER proteostasis capacity, and disease specific changes in proteostasis network engagement. We close by providing a brief outlook on underexplored areas of ER proteostasis where mass spectrometry is a tool uniquely primed to further expand our understanding of the regulation and coordination of protein quality control processes in diverse diseases.

内质网 (ER) 负责处理大约三分之一的人类蛋白质组，包括大多数分泌蛋白和膜蛋白，在蛋白质稳态 (proteostasis) 中起着关键作用。ER 蛋白稳态失调与许多疾病状态有关。因此，继续努力阐明 ER 蛋白质量控制的机制，这些机制是由发生在 ER 内和周围的分子伴侣、共同伴侣、蛋白质折叠和运输因子的瞬时和动态蛋白质-蛋白质相互作用介导的。质谱技术的进步在表征和理解这些决定蛋白质质量控​​制机制的蛋白质-蛋白质相互作用方面发挥了关键作用。这里，我们强调了基于质谱的 ER 蛋白质量控制研究在揭示蛋白质稳态网络的拓扑排列、调整 ER 蛋白质稳态能力的压力反应机制以及蛋白质稳态网络参与的疾病特异性变化方面的最新进展。最后，我们简要介绍了 ER 蛋白质稳态的未充分探索领域，其中质谱是一种独特的工具，可进一步扩大我们对多种疾病中蛋白质质量控​​制过程的调节和协调的理解。