Study of APOL1-containing complexes in podocytes

The C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but also increase the risk of developing kidney disease. APOL1 and APOL3 are death-promoting proteins associated with endoplasmic reticulum and Golgi membranes. We report that in podocytes, either expression of APOL1 devoid of C-terminal helix (APOL1) or deletion of APOL3 (APOL3 KO) induce actomyosin reorganization linked to inhibition of phosphatidylinositol-4-phosphate (PI(4)P) synthesis by the Golgi PI(4)-kinase IIIB (PI4KB). Both APOL1 and APOL3 form K+ channels, but only APOL3 exhibited Ca2+-dependent binding to neuronal calcium sensor-1 (NCS-1), promoting NCS-1/PI4KB interaction that strongly activates PI(4)P synthesis. APOL1 C-terminal deletion or mutations increased APOL1 binding to APOL3, affecting APOL3 interaction with NCS-1. Since podocytes of G1 and G2 patients exhibited an APOL1/APOL3KO-like phenotype, APOL1 C-terminal variants may induce kidney disease by preventing APOL3 from activating PI4KB, resulting in actomyosin reorganization of podocytes.