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

Abstract

Highlights d C-terminal helix alteration unfolds APOL1, increasing APOL1 interaction with APOL3 d APOL3 binds to NCS-1, promoting NCS-1-PI4KB interaction and PI4KB activation d C-terminal APOL1 variants interfere with APOL3-NCS-1 interaction, inactivating PI4KB d PI4KB inactivation occurs in podocytes from kidney disease patients with APOL1 variants

The Mechanism of Kidney Disease Due to APOL1 Risk Variants

“…2 ApoL3 was found to stimulate Golgi PI(4)P synthesis by PI4KB, and C-terminal apoL1 variants exhibit interaction with apoL3 due to increased hydrophobicity. 2 Thus, the apoL1 variants appear to inhibit the PI4KB-stimulating activity of apoL3 through apoL3 binding. 2 The reduction of PI(4)P levels is known to affect actomyosin activity and cellular mobility.…”

“…2 Thus, the apoL1 variants appear to inhibit the PI4KB-stimulating activity of apoL3 through apoL3 binding. 2 The reduction of PI(4)P levels is known to affect actomyosin activity and cellular mobility. 3 Moreover, type I IFN strongly stimulates the expression of apoL1 and apoL3, and these proteins are involved in the initiation of autophagy, mitochondrial fission, and apoptosis.…”

“…1 In podocytes, either truncation of the C-terminal helix of apoL1 or deletion of apoL3 similarly induces reorganization of actomyosin activity, resulting in a reduction of their cellular size and adherence, and an increase of motility. 2 This phenotype is linked to a reduction of Golgi phosphatidylinositol-4-phosphate [PI(4)P] levels, suggesting inactivation of the Golgi phosphatidylinositol 4-kinase PI4KB. In various podocyte lines derived from G1, G2, or G1/G2 patients, significant reduction of Golgi PI(4)P levels has also been observed.…”

“…3 Moreover, type I IFN strongly stimulates the expression of apoL1 and apoL3, and these proteins are involved in the initiation of autophagy, mitochondrial fission, and apoptosis. 2,4,5 Such activities may depend on the apoL3-mediated control of PI4KB, because autophagy and mitochondrial fission are dependent on the transfer of PI4KB-containing vesicles carrying the autophagy marker ATG9A from the Golgi to the endoplasmic reticulum (ER). 4,6,7 Thus, podocyte dysfunctions could result from interference of apoL1 G1/ G2 variants with PI4KB activity.…”

“…8 This finding is in keeping with the toxicity exhibited by wild-type apoL1 when ingested in trypanosomes or transfected in yeast or Escherichia coli. 2 In this respect, it is worth noting that the strong increase of apoL1 expression induced by the viral mimetic poly(I:C) is linked to apoL1 involvement in apoptosis. 2,5 It is tempting to propose that, as occurs for apoptotic Bcl2 proteins, 9 apoL oligomerization resulting from high protein expression triggers the formation of mitochondrial megapores.…”