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The Polycystin-1, Lipoxygenase, and α-Toxin Domain Regulates Polycystin-1 Trafficking

Yaoxian Xu1, Andrew J Streets2, Andrea M Hounslow3

  • 1Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, United Kingdom; Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom;

Journal of the American Society of Nephrology : JASN
|August 28, 2015
PubMed

Insights

The polycystin-1 (PC1) PLAT domain targets PC1 to the plasma membrane by binding lipids. Phosphorylation regulates PC1 internalization, impacting kidney development and function.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Nephrology

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of kidney failure, linked to polycystin-1 (PC1) mutations.
  • The precise function of PC1, particularly its intracellular domains, remains largely unknown.

Purpose of the Study:

  • To elucidate the role of the polycystin-1, lipoxygenase, and α-toxin (PLAT) signature domain of PC1.
  • To investigate the molecular mechanisms governing PC1 localization and function in renal epithelial cells.

Main Methods:

  • Nuclear magnetic resonance (NMR) spectroscopy
  • Biochemical assays
  • Cellular imaging
  • In vivo functional studies

Main Results:

  • The PLAT domain mediates PC1 localization to the plasma membrane via binding to phosphatidylserine and PI4P.
  • Protein kinase A phosphorylation of the PLAT domain inhibits PI4P binding, promoting PC1 internalization through β-arrestin and AP2 recruitment.
  • PC1 internalization is regulated by phosphorylation, suggesting a link to renal homeostasis.

Conclusions:

  • The PC1-PLAT domain plays a critical role in targeting PC1 to the plasma membrane in polarized renal epithelial cells.
  • Phosphorylation-dependent internalization of PC1 is a key regulatory mechanism influencing its function in kidney development and homeostasis.

Keywords:
autosomal dominant polycystic kidney diseasegenetics and developmentpolycystic kidney disease

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