APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes
APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes
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DOI：
10.1681/asn.2016050546
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发表时间：
2017-04-01
影响因子：
13.6
通讯作者：
Skorecki, Karl
中科院分区：
文献类型：
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作者：
Kruzel-Davila, Etty;Shemer, Revital;Skorecki, Karl
APOL 1含有C-末端序列变体（G1和G2），这是撒哈拉以南非洲血统人群肾脏疾病风险增加的主要原因。风险变体的表达也已被证明会导致足细胞和其他细胞类型的损伤，但其潜在机制尚不清楚。我们使用果蝇和酿酒酵母来帮助阐明这些机制。人APOL 1 G1和G2疾病风险等位基因的普遍表达导致D. G 0非风险APOL 1等位基因没有影响，对应于人类疾病风险模式。我们还观察到一个一致的模式与APOL 1的组织特异性表达的细胞损伤。特别是，在D.黑腹肾细胞引起细胞自主积累的内吞示踪剂心房利钠因子-红色荧光蛋白在早期阶段和肾细胞损失在后期阶段。我们还观察到，在S.酿酒酵母，包括损害液泡酸化。酵母菌株内体运输或细胞器酸化缺陷，但不是那些缺陷的自噬显示增强APOL 1毒性与所有亚型。这种模式的差异损伤的APOL 1风险等位基因相比，在进化上不同的物种的non-risk等位基因是保守的核心细胞内的内体运输过程的损害是一致的。这一发现将有助于在这些可行的实验平台中识别细胞损伤途径和相应的治疗靶点。
APOL1 harbors 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 used Drosophila melanogaster and Saccharomyces cerevisiae to help clarify these mechanisms. Ubiquitous expression of the human APOL1 G1 and G2 disease risk alleles caused near-complete lethality in D. melanogaster, with no effect of the G0 nonrisk APOL1 allele, 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 in D. melanogaster nephrocytes 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 the APOL1 risk variants compared with the APOL1 nonrisk variants in S. 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.