PDF(Pubmed)
Abstract：
The endoplasmic reticulum acetylation machinery has emerged as a new branch of the larger endoplasmic reticulum quality control system. It regulates the selection of correctly folded polypeptides as well as reticulophagy-mediated removal of toxic protein aggregates with the former being a particularly important aspect of the proteostatic functions of endoplasmic reticulum acetylation. Essential to this function is the Nε-lysine acetyltransferase activity of acetyltransferase 1 and acetyltransferase 2, which regulates the induction of endoplasmic reticulum-specific autophagy through the acetylation of the autophagy-related protein 9A. Here, we used three mouse models of Charcot-Marie-Tooth disease, peripheral myelin protein 22/Tr-J, C3-peripheral myelin protein 22 and myelin protein zero/ttrr, to study spatial and translational selectivity of endoplasmic reticulum acetyltransferase inhibitors. The results show that inhibition of the endoplasmic reticulum acetyltransferases selectively targets misfolding/pro-aggregating events occurring in the lumen of the organelle. Therefore, they establish acetyltransferase 1 and acetyltransferase 2 as the first proven targets for disease-causing proteotoxic states that initiate within the lumen of the endoplasmic reticulum/secretory pathway.
摘要：
内质网乙酰化机制已成为较大的内质网质量控制系统的新分支。它调节正确折叠的多肽的选择以及网状吞噬介导的毒性蛋白聚集体的去除，前者是内质网乙酰化的蛋白抑制功能的特别重要的方面。该功能的关键是乙酰转移酶1和乙酰转移酶2的Nε-赖氨酸乙酰转移酶活性，其通过自噬相关蛋白9A的乙酰化调节内质网特异性自噬的诱导。这里,我们使用了三种Charcot-Marie-Tooth病小鼠模型,外周髓鞘蛋白22/Tr-J,C3-外周髓鞘蛋白22和髓鞘蛋白零/ttrr，研究内质网乙酰转移酶抑制剂的空间和翻译选择性。结果表明,内质网乙酰转移酶的抑制选择性地靶向发生在细胞器内腔中的错误折叠/促聚集事件。因此,他们将乙酰转移酶1和乙酰转移酶2确立为在内质网/分泌途径内腔内启动的致病蛋白毒性状态的第一个被证实的靶标.
