# Proteostatic regulation of disease-causing polycystin 2 variants

> **NIH NIH R03** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $117,375

## Abstract

My long-term goal has been to investigate the quality control mechanisms that regulate the levels of disease-
causing proteins in the kidney. My most recent project has focused on polycystin 2 (PC2). PC2 plays a vital role
in regulating calcium homeostasis, but mutations in the PKD2 gene, which encodes PC2, can lead to autosomal
dominant polycystic kidney disease (ADPKD). ADPKD is characterized by the formation of large fluid-filled cysts
in the kidney, thereby decreasing kidney function. There is no cure for this disease. However, a deeper
understanding of how mutations alter the fate of the PC2 protein will provide insight into novel treatments for
ADPKD. Interestingly, the majority of PC2 is found in the endoplasmic reticulum (ER), but some of the protein
travels through the secretory pathway to the plasma membrane. One pathway that controls the fate of proteins
in the ER is endoplasmic reticulum-associated degradation (ERAD). During ERAD, misfolded proteins are
recognized by molecular chaperones, polyubiquitinated, and retrotranslocated from the ER membrane for
degradation by the cytoplasmic proteasome. The importance of ERAD to human health is highlighted by the
discovery of >70 disease-associated proteins that are targeted to this pathway, many of which are channels and
transporters. Indeed, my preliminary data suggest—for the first time—that ERAD plays a central role in regulating
the biogenesis of select PC2 missense mutants that are disease-causing. To elucidate how these proteins are
targeted for destruction, I will use a powerful combination of genetic, biochemical, and physiological methods
and will develop new experimental tools. My overall hypothesis is that select missense mutations in PC2
are targeted to the ERAD pathway by molecular chaperones, for which therapeutics are currently being
developed, as well as by other components of the “protein quality control” machinery in the cell. To test
this hypothesis, the specific aims of this proposal are: (1) To establish a yeast PC2 expression system, which
allow me to coopt facile genetic approaches and then define how PC2 missense mutants are targeted for ERAD.
Discoveries from this attack will next be confirmed in renal epithelial cell culture systems; and (2) To develop a
new yeast screen in which novel genetic modifiers of PC2 protein turnover can be identified and in which a whole
genomic analysis can be undertaken. Hits from this screen will be evaluated in the future in cell culture and
rodent models. This project will identify the molecular mechanisms that lead to ADPKD in patients who carry a
defined group of PC2 mutations and, in the long-term, uncover a range of potential therapeutics.

## Key facts

- **NIH application ID:** 10092157
- **Project number:** 5R03DK124659-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Christopher James Guerriero
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $117,375
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092157

## Citation

> US National Institutes of Health, RePORTER application 10092157, Proteostatic regulation of disease-causing polycystin 2 variants (5R03DK124659-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10092157. Licensed CC0.

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