ABSTRACT The nucleus is enclosed by a double-membrane structure, the nuclear envelope, which separates the nucleoplasm from the cytoplasm. The outer nuclear membrane is continuous with the endoplasmic reticulum (ER), whereas the inner nuclear membrane (INM) is a specialized compartment with a unique proteome. In order to ensure compartmental homeostasis, INM-associated degradation (INMAD) is required for both protein quality control and regulated proteolysis of INM proteins. INMAD shares similarities with ER-associated degradation (ERAD). The mechanism of ERAD is well characterized, whereas the INMAD pathway requires further definition. Here we review the three different branches of INMAD, mediated by their respective E3 ubiquitin ligases: Doa10, Asi1-3, and APC/C. We clarify the distinction between ERAD and INMAD, their substrate recognition signals, and the subsequent processing by their respective degradation machineries. We also discuss the significance of cell-cycle and developmental regulation of protein clearance at the INM, and its relationship to human disease.

中文翻译：

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内核膜相关蛋白质降解的调节：来自芽殖酵母的经验教训

摘要 细胞核被双膜结构包围，即核膜，它将核质与细胞质分开。外核膜与内质网 (ER) 连续，而内核膜 (INM) 是具有独特蛋白质组的专门隔室。为了确保区室稳态，蛋白质质量控​​制和 INM 蛋白质的调节蛋白水解都需要 INM 相关降解 (INMAD)。INMAD 与 ER 相关降解 (ERAD) 有相似之处。ERAD 的机制得到了很好的表征，而 INMAD 途径需要进一步定义。在这里，我们回顾了 INMAD 的三个不同分支，由它们各自的 E3 泛素连接酶介导：Doa10、Asi1-3 和 APC/C。我们澄清了 ERAD 和 INMAD 之间的区别，它们的底物识别信号，以及它们各自的降解机器的后续处理。我们还讨论了细胞周期和 INM 蛋白质清除的发育调节的重要性，及其与人类疾病的关系。