RESCUING MEMBRANE TRAFFICKING DEFICIENCY OF MUTANT HERG1 K<SUP>+</SUP> CHANNELS

The human ether-à-go-go-related gene (hERG1) K⁺ channel, encoded by the KCNH2 gene, is essential for repolarization of action potentials in cardiomyocytes. Emerging evidence indicates that hERG1 is also expressed in various regions in the brain and critically regulates neuronal excitability. Loss-of-function mutations in KCNH2 are linked to the arrhythmogenic cardiac disorder type 2 long QT syndrome (LQT2) that can be attributed to cardiac hyperexcitability. Recent genetic linkage studies further support a correlation between KCNH2 variants (either LQT2-related or unrelated) and epilepsy and seizures, highlighting the physiological importance of hERG1 K⁺ channel in stabilizing neural circuits. The majority of disease-related KCNH2 mutations are associated with hERG1 protein misfolding and trafficking defects, leading to enhanced endoplasmic reticulum (ER)-associated degradation. Here, we aimed to investigate the molecular mechanism governing hERG1 proteostasis in the ER, as well as exploring strategies to rescue the trafficking defect of mutant hERG1 channels. We identified the E3 ubiquitin ligase RNF61 as a negative regulator of hERG1 proteostasis in the ER, promoting ubiquitin-proteasome–dependent degradation of core-glycosylated, immature hERG1 protein. Genetic downregulation of RNF61 notably increased hERG1 protein expression. Pharmacological inhibition of RNF61 using either a clinically established drug or a pleiotropic bioactive phytomedicine enhanced the maturation and plasma membrane delivery of trafficking-deficient hERG1 mutants. Together, these findings establish RNF61 as a novel modulator of hERG1 proteostasis in the ER and suggest that suppressing RNF61–mediated proteasomal degradation may effectively restore functional expression of trafficking-deficient hERG1 mutant channels in cardiomyocytes and neurons.