APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes.

摘要: APOL1 harbors C-terminal sequence variants (G1 and G2), which account for much of the increased risk kidney disease in sub-Saharan African ancestry populations. Expression has also been shown to cause injury podocytes other cell types, but underlying mechanisms are not understood. We used Drosophila melanogaster Saccharomyces cerevisiae help clarify these mechanisms. Ubiquitous expression human G1 G2 alleles caused near-complete lethality D. melanogaster, with no effect G0 nonrisk allele, corresponding pattern risk. observed a congruent cellular damage tissue-specific APOL1. In particular, nephrocytes cell-autonomous accumulation endocytic tracer atrial natriuretic factor-red fluorescent protein at early stages nephrocyte loss later stages. differential toxicity compared S. cerevisiae, including impairment vacuole acidification. Yeast strains defective endosomal trafficking or organelle acidification those autophagy displayed augmented all isoforms. This by across evolutionarily divergent species is consistent an conserved core intracellular processes. finding should facilitate identification pathways therapeutic targets interest amenable experimental platforms.