Congenital long QT syndrome (LQTS) is a heart channel disease associated with fatal ventricular arrhythmias or cardiac arrest. Human ether-a-go-go-related gene (HERG) mutation is one of the main causes in type 2 LQTS since it may lead to abundant immature HERG channel protein accumulate in the endoplasmic reticulum (ER). In our study, we have successfully constructed the G604S-HERG mutation in HEK293 cells and demonstrated that the immature HERG protein on ER via Western blot and immunofluorescence. Herein we found that unfolded protein reaction (UPR) process has been activated in order to counter this endoplasmic reticulum stress (ERS) since the main sensors got upregulated. Meanwhile, autophagy was also observed in this process and verified by Western blot and transmission electron microscopy. To explore the relationship underlying autophagy and UPR in the condition of ERS, we found that PERK-EIF2α-CHOP axis was activated. Our findings provides insight for G604S-HERG mutation in type 2 LQTS.

中文翻译：

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LQT2 中的 G604S-HERG 突变通过 UPR 相关途径导致自噬

先天性长 QT 综合征 (LQTS) 是一种与致命性室性心律失常或心脏骤停相关的心脏通道疾病。人类 ether-a-go-go 相关基因 (HERG) 突变是 2 型 LQTS 的主要原因之一，因为它可能导致大量未成熟的 HERG 通道蛋白在内质网 (ER) 中积累。在我们的研究中，我们成功构建了 HEK293 细胞中的 G604S-HERG 突变，并通过蛋白质印迹和免疫荧光证明了 ER 上的未成熟 HERG 蛋白。在此，我们发现未折叠蛋白反应 (UPR) 过程已被激活以对抗这种内质网应激 (ERS)，因为主要传感器被上调。同时，在此过程中也观察到自噬，并通过蛋白质印迹和透射电子显微镜进行验证。为了探讨 ERS ​​条件下自噬和 UPR 的关系，我们发现 PERK-EIF2α-CHOP 轴被激活。我们的发现为 2 型 LQTS 中的 G604S-HERG 突变提供了见解。