title: APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes.
abstract: APOL1harbors C-terminal sequence variants (G1 and G2), which account for much of the increased risk for kidney disease in sub-Saharan African ancestry populations. Expression of the risk variants has also been shown to cause injury to podocytes and other cell types, but the underlying mechanisms are not understood. We usedDrosophila melanogasterandSaccharomyces cerevisiaeto help clarify these mechanisms. Ubiquitous expression of the human APOL1 G1 and G2 disease risk alleles caused near-complete lethality inD. melanogaster, with no effect of the G0 nonriskAPOL1allele, corresponding to the pattern of human disease risk. We also observed a congruent pattern of cellular damage with tissue-specific expression of APOL1. In particular, expression of APOL1 risk variants inD. melanogasternephrocytes caused cell-autonomous accumulation of the endocytic tracer atrial natriuretic factor-red fluorescent protein at early stages and nephrocyte loss at later stages. We also observed differential toxicity of theAPOL1risk variants compared with theAPOL1nonrisk variants inS. cerevisiae, including impairment of vacuole acidification. Yeast strains defective in endosomal trafficking or organelle acidification but not those defective in autophagy displayed augmented APOL1 toxicity with all isoforms. This pattern of differential injury by the APOL1 risk alleles compared with the nonrisk alleles across evolutionarily divergent species is consistent with an impairment of conserved core intracellular endosomal trafficking processes. This finding should facilitate the identification of cell injury pathways and corresponding therapeutic targets of interest in these amenable experimental platforms.
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel; Departments of.
authors.forename: Etty
authors.initials: E
authors.lastname: Kruzel-Davila
authors.affiliation: Genetics and Developmental Biology and.
authors.forename: Revital
authors.initials: R
authors.lastname: Shemer
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel; Departments of.
authors.forename: Ayala
authors.initials: A
authors.lastname: Ofir
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel; Departments of.
authors.forename: Ira
authors.initials: I
authors.lastname: Bavli-Kertselli
authors.affiliation: Genetics and Developmental Biology and.
authors.forename: Ilona
authors.initials: I
authors.lastname: Darlyuk-Saadon
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel; Departments of.
authors.forename: Pazit
authors.initials: P
authors.lastname: Oren-Giladi
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel; Departments of.|Department of Nephrology, Mayanei HaYeshua Medical Center, Bnei Brak, Israel.
authors.forename: Walter G
authors.initials: WG
authors.lastname: Wasser
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel; Departments of.|Genetics and Developmental Biology and.
authors.forename: Daniella
authors.initials: D
authors.lastname: Magen
authors.affiliation: Genetics and Developmental Biology and.
authors.forename: Eid
authors.initials: E
authors.lastname: Zaknoun
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; and.
authors.forename: Maya
authors.initials: M
authors.lastname: Schuldiner
authors.affiliation: Genetics and Developmental Biology and.
authors.forename: Adi
authors.initials: A
authors.lastname: Salzberg
authors.affiliation: Microbiology and Inflammation, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kornitzer
authors.affiliation: Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris, France.
authors.forename: Zvonimir
authors.initials: Z
authors.lastname: Marelja
authors.affiliation: Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris, France.
authors.forename: Matias
authors.initials: M
authors.lastname: Simons
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel; Departments of skorecki@tx.technion.ac.il.|Genetics and Developmental Biology and.
authors.forename: Karl
authors.initials: K
authors.lastname: Skorecki
mesh_terms: D000483:Alleles; D000818:Animals; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D004331:Drosophila melanogaster / Q000166:cytology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000166:cytology
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL
keywords: Apolipoprotein L1; acidification; chronic kidney disease; endocytic trafficking; nephrocyte