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首页> 外文期刊>American Journal of Physiology >BH3 domain-independent apolipoprotein LI toxicity rescued by BCL2 prosurvival proteins
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BH3 domain-independent apolipoprotein LI toxicity rescued by BCL2 prosurvival proteins

机译：BCH3域无关的载脂蛋白李毒性被BCL2脱水蛋白救出

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摘要

The potent trypanolytic properties of human apolipoprotein LI (APOLl) can be neutralized by the trypanosome variant surface antigen gene product known as serum resistance-associated protein. However, two common APOLl haplotypes present uniquely in individuals of West African ancestry each encode APOLl 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 APOLl, recessive inheritance of these two trypanoprotective APOLl alleles predisposes to kidney disease. Proposed mechanisms of APOLl toxicity have included BH3 domain-dependent autophagy and/or ion channel activity. We probed these potential mechanisms by expressing APOLl in Xenopus laevis oocytes. APOLl expression in oocytes increased ion permeability and caused profound morphological deterioration (toxicity). Coexpression of BCL2 family members rescued APOLl-associated oocyte toxicity in the order MCL1 ~ BCLW > BCLXL ~ BCL2A1 ? BCL2. Deletion of nine nominal core BH3 domain residues abolished APOLl-asso-ciated toxicity, but missense substitution of the same residues abolished neither oocyte toxicity nor its rescue by coexpressed MCL1. The APOLl BH3 domain was similarly dispensable for the ability of APOLl to rescue intact mice from lethal trypanosome challenge. Replacement of most extracellular Na+ by K+ also reduced APOLl-associated oocyte toxicity, allowing demonstration of APOLl-associated increases in Ca2+ and Cl~ fluxes and oocyte ion currents, which were similarly reduced by MCL1 coexpression. Thus APOLl toxicity in Xenopus oocytes is BH3-independent, but can nonetheless be rescued by some BCL2 family proteins.
机译：人载脂蛋白Li（Apoll）的有效胰蛋白酶特性可通过称为血清抗性相关蛋白的锥虫体变体表面抗原基因产物中和。然而，两种常见的奥尔单倍型在西非祖先的个体中唯一地存在，每种编码抗血清抗性相关蛋白的奥林变体，并且每个都会赋予人类非洲睡眠疾病的大量抵抗力。与阿霍尔的主要遗传抗锥体活性相比，这两种锥虫保护剂的隐性遗传性促使肾病。提出的胃胃毒性机制包括BH3依赖性自噬和/或离子通道活性。我们通过在Xenopus Laevis卵母细胞中表达Apoll来探讨这些潜在机制。卵母细胞中的Apoll表达增加了离子渗透性，引起了深刻的形态劣化（毒性）。 BCL2家族成员的共同表达在命令MCL1〜BCLW> BCLXL〜BCL2A1中拯救了Apoll相关的卵母细胞毒性？ BCL2。删除九个标称核心BH3结构域残留物废除了Apoll-Asso-CiEd的毒性，但是相同残留物的畸形取代既不废除卵母细胞毒性也不通过共同抑制的MCL1拯救。 Apoll BH3结构域同样可分配，以便Apoll拯救从致死的脑体组攻击中拯救完整小鼠的能力。替代大多数细胞外Na +通过K +也降低了孔孔相关的卵母细胞毒性，允许通过MCl1共表达类似地减少Ca2 +和Cl〜助熔剂和卵母细胞离子电流的Apoll相关增加。因此，卵脓性卵母细胞中的胃毒性是无关的，但尽管如此，可以通过一些BCl2家族蛋白来救出。

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