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Abstract: TH-PO667

Quality Control of Polycystin 2 Missense Mutants in the Endoplasmic Reticulum

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Guerriero, Christopher J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Brodsky, Jeffrey L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder and is a leading cause of end-stage renal disease. ADPKD arises from mutations in the PKD1 and PKD2 genes, encoding the primary ciliary proteins polycystin 1 (PC1) and polycystin 2 (PC2), respectively. Myriad mutations have been documented throughout the PKD loci, ultimately resulting in aberrant signaling, cell proliferation, and fluid secretion. In addition to the primary cilium, PC2 also localizes to the endoplasmic reticulum (ER). Given PC2’s large size, topological complexity, and localization, we hypothesize that PC2 missense mutants may misfold and be turned over by the endoplasmic reticulum-associated degradation (ERAD) pathway. ERAD triages newly synthesized aberrant proteins and directs misfolded or misassembled confomers for degradation via the ubiquitin proteasome system. Due to an incomplete understanding of the factors that influence early events during PC2 maturation, we investigated PC2 biogenesis in the genetically-tractable model system, S. cerevisiae.


We have established a yeast expression system for 3XHA-PC2 to study the early biosynthetic decisions that mediate the folding, maturation, and degradation of PC2 missense mutants. Disease-causing PC2 variants were generated by site-directed mutagenesis, expressed in S. cerevisiae, and their metabolism was examined using cycloheximide chase analysis. Results from the yeast model were further confirmed via transient transfection of GFP-PC2 into HEK293 cells.


Our preliminary data indicate that select PC2 missense mutants are more rapidly degraded in both yeast and HEK293 cells relative to wild type PC2. Moreover, unstable PC2 mutants are more highly poly-ubiquitinated than wild type PC2. In addition, following treatment with the proteasome inhibitor MG132, the level of polyubiquitinated protein increases to a greater extent for PC2 missense variants, suggesting selective turnover by the proteasome.


The findings support our hypothesis that PC2 missense mutants are ERAD substrates. Given recent interest in the development of protein folding modulators for other ERAD-related diseases, our data provide a promising hint that the maturation of some PC2 missense mutants may be amenable to pharmacological correction. Funded by NIDDK101584 to CJG and NIDDK079307 to JLB.


  • NIDDK Support