The function of apolipoproteins L (APOLs): relevance for kidney disease, neurotransmission disorders, cancer and viral infection

Abstract

The discovery that apolipoprotein L1 (APOL1) is the trypanolytic factor of human serum raised interest about the function of APOLs, especially following the unexpected finding that in addition to their protective action against sleeping sickness, APOL1 C-terminal variants also cause kidney disease. Based on the analysis of the structure and trypanolytic activity of APOL1, it was proposed that APOLs could function as ion channels of intracellular membranes and be involved in mechanisms triggering programmed cell death. In this review, the recent finding that APOL1 and APOL3 inversely control the synthesis of phosphatidylinositol-4-phosphate (PI(4)P) by the Golgi PI(4)-kinase IIIB (PI4KB) is commented. APOL3 promotes Ca 2+-dependent activation of PI4KB, but due to their increased interaction with APOL3, APOL1 C-terminal variants can inactivate APOL3, leading to reduction of Golgi PI(4)P synthesis. The impact of APOLs on several pathological processes that depend on Golgi PI(4)P levels is discussed. I propose that through their effect on PI4KB activity, APOLs control not only actomyosin activities related to vesicular trafficking, but also the generation and elongation of autophagosomes induced by inflammation.

The Mechanism of Kidney Disease Due to APOL1 Risk Variants

“…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.…”

“…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. This conclusion differs from that of many studies, which have concluded that G1 and G2 induce nonspecific cytotoxicity.…”

“…10 As occurs for Bcl2 homologous antagonist killer (Bak) or Bcl2-associated X (Bax), hydrophobic residues exposed on apoL1 helices may contribute to generate lipidic membrane pores by surface interaction with cardiolipin (CL). 4,9 c In podocytes, intracellular apoL1 is processed differently from the secreted version of this protein (isoform 1). 2 ApoL1 isoform 3, which is encoded by a transcript variant, is not targeted to the secretory pathway, but resides at the cytoplasmic face of the ER, together with apoL3.…”

“…Under starvation or inflammatory conditions like viral infection, induction of autophagy and mitochondrial fission occur through actomyosin-driven transfer of PI4KB-carrying ATG9A vesicles from the Golgi to the ER, coupled with the reciprocal transfer of the PI(4)P phosphatase Suppressor of actin (Sac1) from the ER to the Golgi. 4,6,7,26,27 Thus, the site of PI(4)P synthesis moves from the Golgi to the ER to trigger expansion of autophagy membranes rather than expansion of vesicular membranes. Inhibition of PI4KB at the ER-mitochondrion contact sites (MERCs) interferes with initiation of autophagy and mitochondrial membrane fusion/fission activities, preventing autophagy-mediated rescue from infection damage (hit 2).…”

“…This could account for the genetic association of apoLs with neurotransmission disorders. 4 Thus, it seems worth investigating whether neurotransmission is affected in G1 or G2 individuals.…”