BH3 domain-independent apolipoprotein L1 toxicity rescued by BCL2 prosurvival proteins
BH3 domain-independent apolipoprotein L1 toxicity rescued by BCL2 prosurvival proteins
复制标题
DOI：
10.1152/ajpcell.00142.2015
复制
发表时间：
2015-09-01
影响因子：
5.5
通讯作者：
Alper, S. L.
中科院分区：
文献类型：
--
作者：
Heneghan, J. F.;Vandorpe, D. H.;Alper, S. L.
人类载脂蛋白L1 （APOL1）的强效抗锥虫特性可以被称为血清抗性相关蛋白的锥虫变异表面抗原基因产物中和。然而，两种常见的APOL1单倍型在西非血统个体中独特存在，每种都编码对血清抗性相关蛋白具有抗性的APOL1变体，并且每种都赋予对人类非洲昏睡病的实质性抗性。与APOL1的显性遗传抗锥虫活性相反，这两个保护锥虫的APOL1等位基因的隐性遗传易导致肾脏疾病。已提出的APOL1毒性机制包括BH3结构域依赖性自噬和/或离子通道活性。我们通过在非洲爪蟾卵母细胞中表达APOL1来探讨这些潜在的机制。APOL1在卵母细胞中的表达增加了离子通透性，引起了严重的形态恶化（毒性）。BCL2家族成员的共表达挽救了apol1相关的卵母细胞毒性，其顺序为MCL1类似于BCLW类似于BCLXL类似于BCL2A1 >> BCL2。删除9个名义核心BH3结构域残基可以消除apol1相关的毒性，但对相同残基的错义替换既不能消除卵母细胞毒性，也不能消除共表达MCL1对卵母细胞的拯救作用。同样，APOL1 BH3结构域对于APOL1从致命的锥虫攻击中拯救完整小鼠的能力也是必不可少的。用K+替代大部分细胞外Na+也降低了与apol1相关的卵母细胞毒性，从而证明了与apol1相关的Ca2+和Cl-通量和卵母细胞离子电流的增加，这同样被MCL1共表达降低。因此，APOL1对爪蟾卵母细胞的毒性与bh3无关，但仍然可以通过一些BCL2家族蛋白来挽救。
The potent trypanolytic properties of human apolipoprotein L1 (APOL1) can be neutralized by the trypanosome variant surface antigen gene product known as serum resistance-associated protein. However, two common APOL1 haplotypes present uniquely in individuals of West African ancestry each encode APOL1 variants resistant to serum resistance-associated protein, and each confers substantial resistance to human African sleeping sickness. In contrast to the dominantly inherited anti-trypanosomal activity of APOL1, recessive inheritance of these two trypanoprotective APOL1 alleles predisposes to kidney disease. Proposed mechanisms of APOL1 toxicity have included BH3 domain-dependent autophagy and/or ion channel activity. We probed these potential mechanisms by expressing APOL1 in Xenopus laevis oocytes. APOL1 expression in oocytes increased ion permeability and caused profound morphological deterioration (toxicity). Coexpression of BCL2 family members rescued APOL1-associated oocyte toxicity in the order MCL1 similar to BCLW similar to BCLXL similar to BCL2A1 >> BCL2. Deletion of nine nominal core BH3 domain residues abolished APOL1-associated toxicity, but missense substitution of the same residues abolished neither oocyte toxicity nor its rescue by coexpressed MCL1. The APOL1 BH3 domain was similarly dispensable for the ability of APOL1 to rescue intact mice from lethal trypanosome challenge. Replacement of most extracellular Na+ by K+ also reduced APOL1-associated oocyte toxicity, allowing demonstration of APOL1-associated increases in Ca2+ and Cl- fluxes and oocyte ion currents, which were similarly reduced by MCL1 coexpression. Thus APOL1 toxicity in Xenopus oocytes is BH3-independent, but can nonetheless be rescued by some BCL2 family proteins.