FIGURE 9.

Scheme of role of Ub in endocytic degradation of hERG channels. Under low K⁺ conditions, mature hERG channels adopt a non-conducting conformation, leading to monoubiquitination, which triggers hERG endocytosis through a caveolin-dependent pathway. Endocytosed hERG channels transit through early endosomes into MVBs. While Vps24 is critical for the formation and sorting of monoubiquitinated hERG channels into MVBs, STAMBP deubiquitinates the monoubiquitinated hERG to facilitate hERG sorting in the MVBs. The sorted hERG is deposited in the lysosomes for degradation. Lactacystin prevents deubiquitination, leading to accumulation of monoubiquitinated hERG channels which are primarily localized in the plasma membrane. Bafilomycin A1 prevents hERG degradation in lysosomes, leading to accumulation of deubiquitinated hERG in lysosomes.