Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, 6041 Gosselies, Belgium.
Laboratory of Experimental Medicine (ULB222), CHU Charleroi, Université Libre de Bruxelles, Montigny le Tilleul, Belgium.
Cell Rep. 2020 Mar 17;30(11):3821-3836.e13. doi: 10.1016/j.celrep.2020.02.064.
The C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but they also increase the risk of kidney disease. APOL1 and APOL3 are death-promoting proteins that are partially associated with the endoplasmic reticulum and Golgi membranes. We report that in podocytes, either APOL1 C-terminal helix truncation (APOL1Δ) or APOL3 deletion (APOL3KO) induces similar actomyosin reorganization linked to the inhibition of phosphatidylinositol-4-phosphate [PI(4)P] synthesis by the Golgi PI(4)-kinase IIIB (PI4KB). Both APOL1 and APOL3 can form K channels, but only APOL3 exhibits Ca-dependent binding of high affinity to neuronal calcium sensor-1 (NCS-1), promoting NCS-1-PI4KB interaction and stimulating PI4KB activity. Alteration of the APOL1 C-terminal helix triggers APOL1 unfolding and increased binding to APOL3, affecting APOL3-NCS-1 interaction. Since the podocytes of G1 and G2 patients exhibit an APOL1Δ or APOL3KO-like phenotype, APOL1 C-terminal variants may induce kidney disease by preventing APOL3 from activating PI4KB, with consecutive actomyosin reorganization of podocytes.
载脂蛋白 L1（APOL1）的 C 端变体 G1 和 G2 赋予人类抵抗罗得西亚锥虫（Trypanosoma rhodesiense）睡眠病寄生虫的抗性，但它们也增加了患肾病的风险。APOL1 和 APOL3 是促进细胞死亡的蛋白质，它们部分与内质网和高尔基体膜相关联。我们报告在足细胞中，APOL1 C 端螺旋截断（APOL1Δ）或 APOL3 缺失（APOL3KO）诱导类似的肌动球蛋白重排，这与高尔基体 PI(4)激酶 IIIB（PI4KB）抑制磷脂酰肌醇-4-磷酸 [PI(4)P] 的合成有关。APOL1 和 APOL3 都可以形成 K 通道，但只有 APOL3 表现出对神经元钙传感器-1（NCS-1）的高亲和力 Ca 依赖性结合，促进 NCS-1-PI4KB 相互作用并刺激 PI4KB 活性。APOL1 C 端螺旋的改变触发 APOL1 展开和与 APOL3 的结合增加，影响 APOL3-NCS-1 的相互作用。由于 G1 和 G2 患者的足细胞表现出 APOL1Δ 或 APOL3KO 样表型，APOL1 C 端变体可能通过阻止 APOL3 激活 PI4KB 来诱导肾病，随后足细胞的肌动球蛋白重排。
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