Figure 4. Quality control of misfolded hERG at peripheral cellular compartments .

Misfolded hERG cytosolic domains are recognized by cytosolic chaperone proteins such as Hsp/Hsc70 and Hsp90. Chaperone binding results in recruitment of CHIP E3 ubiquitin ligase and subsequent ubiquitination. Polyubiquitin serves as a signal for rapid internalization via a clathrin‐independent mechanism. Possible pathways include recruitment to lipid rafts and subsequent caveolin‐mediated internalization or an Arf6‐dependent mechanism. Internalized proteins may be prevented from recycling back to the plasma membrane and are instead sorted to intraluminal vesicles and targeted for lysosomal degradation by the ESCRT machinery.