KCNH2A561V Heterozygous Mutation Inhibits KCNH2 Protein Expression via The Activation of UPR Mediated by ATF6

• DOI: 10.33549/physiolres.935095
• Publication Date: 2023-11-27T13:51:23Z
• Authors: B CHEN; L TAN; D CHEN; X WANG; J LIU; X HUANG; Y WANG; S HUANG; F MAO; J LIAN
• Keywords: ATF6

The potassium channel protein KCNH2 is encoded by gene, and there are more than 300 mutations of KCNH2. Unfolded response (UPR) typically initiated in to an accumulation unfolded and/or misfolded proteins the endoplasmic reticulum (ER). present study aimed explore UPR process role activating transcription factor 6 (ATF6) abnormal expression voltage-gated subfamily H member 2 (KCNH2)A561V. wild-type (wt) A561V mutant was constructed with his-tag. 293 cells were used divided into KCNH2wt+KCNH2A561V, KCNH2wt KCNH2A561V groups. levels ATF6 different groups detected Western blotting, reverse transcription-quantitative PCR, immunofluo-rescence immuno-coprecipitation assays. types abundance samples analyzed mass spectrometry. proteomic analysis spectrometry results carried out using reactome database GO (Gene Ontology) tool. mRNA KCNH2wt+KCNH2A561V group higher compared group. However, full-length inhibited, indicating that highly activated a substantial number sheared control Furthermore, A561V-KCNH2 mutation leading immature form (135 kDa bands) ER, resulting reduction ratio 155 kDa/135 kDa. In addition, UPR-related ‘cysteine biosynthetic activity’ GO:0019344 ‘positive regulation cytoplasmic translation GO:2000767 Hence, co-expression process, which led inhibition synthesis, turn inhibiting These provided theoretical basis for clinical treatment Long QT syndrome.