G604S-HERG mutation in LQT2 leads to autophagy via the UPR-related pathway

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-EIF2a-CHOP axis was activated. Our findings provides insight for G604S-HERG mutation in type 2 LQTS.