Mutation-specific peripheral and ER quality control of hERG channel cell-surface expression

Area of Science:

• Molecular biology
• Cardiovascular research
• Cellular quality control

Background:

• Impaired plasma membrane (PM) expression of the hERG K+ channel causes Long-QT syndrome type-2 (LQT2), increasing cardiac arrhythmia risk.
• Reduced hERG PM expression is mainly linked to endoplasmic reticulum (ER) protein quality control (QC) systems degrading misfolded channels.

Purpose of the Study:

• Investigate the role of post-ER (peripheral) QC pathways in LQT2 pathogenesis.
• Characterize the cellular processing of mildly misfolded hERG variants with partial ER retention and PM expression defects.

Main Methods:

• Studied Per-Arnt-Sim (PAS)-domain mutant hERGs at physiological temperature.
• Analyzed ER-associated degradation (ERAD) and post-ER degradation pathways.
• Utilized pharmacochaperones and low-temperature treatments to assess conformational correction.

Main Results:

• hERG PM expression defects in LQT2 are influenced by both ER and peripheral QC systems.
• PAS-mutants undergo inefficient ER maturation, ubiquitin-proteasomal degradation, and rapid ubiquitin-independent endocytosis and lysosomal degradation.
• Conformational correction via pharmacochaperones or low temperatures restores WT-like hERG trafficking.

Conclusions:

• Aberrant cellular processing of hERG channels in LQT2 is driven by conformational destabilization.
• Both ER and post-ER QC pathways contribute to the loss of hERG PM expression in a subset of LQT2 mutations.