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The Sorting Nexin 3 Retromer Pathway Regulates the Cell Surface Localization and Activity of a Wnt-Activated

Shuang Feng1, Andrew J Streets1, Vasyl Nesin2

  • 1Kidney Genetics Group, Academic Nephrology Unit and the Bateson Centre, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom.

Journal of the American Society of Nephrology : JASN
|June 17, 2017
PubMed

Insights

The retromer complex, including sorting nexin 3 (SNX3), regulates the surface expression of polycystin proteins (PC1 and PC2) involved in autosomal dominant polycystic kidney disease (ADPKD). Targeting this complex may offer new ADPKD therapies.

Area of Science:

  • Cell Biology
  • Molecular Medicine
  • Genetics

Background:

  • Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder caused by mutations in PKD1 or PKD2.
  • The ADPKD proteins, polycystin-1 (PC1) and polycystin-2 (PC2), form a crucial plasma membrane complex.
  • Mechanisms governing PC1 and PC2 subcellular localization remain largely unknown.

Purpose of the Study:

  • To investigate the role of the retromer complex in regulating PC1 and PC2 localization.
  • To identify specific retromer components that interact with PC1 and PC2.
  • To explore the functional consequences of retromer-mediated regulation on PC1 and PC2 activity.

Main Methods:

  • Yeast two-hybrid assays to detect protein-protein interactions.
  • Biochemical assays to confirm binding affinities.
  • Cellular assays (in vitro and in vivo) to assess protein expression and function.
  • Gene knockdown experiments to evaluate the impact of retromer components.

Main Results:

  • PC2 directly binds to two isoforms of sorting nexin 3 (SNX3), a retromer-associated protein.
  • Knockdown of SNX3 or VPS35 (a core retromer protein) increases surface expression of PC1 and PC2.
  • Reduced SNX3 or VPS35 enhances Wnt-activated PC2-dependent ion currents.

Conclusions:

  • An SNX3-retromer complex regulates the surface expression and function of PC1 and PC2.
  • This regulation impacts ion channel activity relevant to ADPKD.
  • Targeting endosomal sorting of PC1 and PC2 presents a potential therapeutic strategy for ADPKD.
Keywords:
ADPKDPKD1PKD2polycystic kidney diseaseretromer

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