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APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin

Sophie Uzureau1, Laurence Lecordier1, Pierrick Uzureau2

  • 1Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 6041 Gosselies, Belgium.

Cell Reports
|March 19, 2020
PubMed

Insights

Apolipoprotein L1 (APOL1) variants linked to kidney disease risk disrupt podocyte function by inhibiting PI4KB, a key enzyme in lipid synthesis. This leads to actomyosin reorganization and potential kidney damage.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Nephrology

Background:

  • Apolipoprotein L1 (APOL1) C-terminal variants (G1, G2) confer resistance to Trypanosoma rhodesiense but increase kidney disease risk.
  • APOL1 and APOL3 are death-promoting proteins associated with the endoplasmic reticulum and Golgi membranes.

Purpose of the Study:

  • To investigate the molecular mechanisms by which APOL1 variants and APOL3 affect podocyte function.
  • To elucidate the role of phosphatidylinositol-4-phosphate (PI(4)P) synthesis and actomyosin organization in APOL1-associated nephropathy.

Main Methods:

  • Studied APOL1 C-terminal helix truncation (APOL1Δ) and APOL3 deletion (APOL3KO) in podocytes.
  • Assessed actomyosin reorganization, PI(4)P synthesis, and protein interactions involving APOL1, APOL3, calcium, and NCS-1.

Main Results:

  • Both APOL1Δ and APOL3KO induced similar actomyosin reorganization linked to inhibited PI(4)P synthesis by PI4KB.
  • APOL3, but not APOL1, binds NCS-1 in a Ca2+-dependent manner, promoting PI4KB activity.
  • APOL1 C-terminal helix alteration increased APOL1 binding to APOL3, impairing APOL3-NCS-1 interaction.

Conclusions:

  • APOL1 C-terminal variants may cause kidney disease by preventing APOL3 from activating PI4KB, leading to podocyte actomyosin reorganization.
  • The findings link APOL1 nephropathy to dysregulated PI4KB activity and cytoskeletal changes in podocytes.
Keywords:
APOL1APOL3MYH9NCS-1PI4KBactomyosin cytoskeletonkidney diseasephosphoinositide controlsleeping sickness

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