Identification of polycystin 2 missense mutants targeted for endoplasmic reticulum-associated degradation

This study indicates that select missense mutations in PC2, a protein that when mutated leads to ADPKD, result in protein misfolding and degradation via the ERAD pathway. Our work leveraged a new yeast model and an HEK293 cell model to discover the mechanism underlying PC2 instability and demonstrates the potential for pharmacological rescue. We also suggest that targeting the protein misfolding phenotype with chemical chaperones may offer new therapeutic strategies to manage ADPKD-related protein dysfunction.