[人类红细胞膜磷脂酰丝氨酸不对称性维持与破坏的机制见解：其生命周期中的生存策略]

摘要(中文译文)

人红细胞在其120天的寿命中，仅将磷脂酰丝氨酸（phosphatidylserine，PS）保留在质膜的内小叶，通过与细胞骨架蛋白结合来增强膜强度。同时，在寿命终点时，PS暴露于外小叶，以便被脾巨噬细胞吞噬清除。因此，红细胞的寿命由PS的定位决定。来自一名ATP11C缺陷患者的红细胞，其PS翻转酶活性降低了90%，然而该患者几乎所有红细胞中PS均未暴露。这提示不依赖翻转酶的机制可能将PS保留在内小叶。在低细胞内Ca条件下，去除红细胞膜中的胆固醇显著促进了PS暴露，表明胆固醇可能阻断脂质 scrambling。在衰老红细胞中，ATP11C水平以及细胞内ATP和K浓度依次降低，从而降低翻转酶活性。与年轻红细胞相比，衰老红细胞在细胞内Ca仅轻微升高时即可轻易暴露PS，表明细胞内Ca浓度升高是决定红细胞寿命的关键因素。我们还评估了肾性贫血患者的红细胞：其红细胞寿命缩短。我们发现，贫血红细胞中ATP11C表达水平和细胞内K浓度降低，表明PS暴露触发了衰老的提前发生。阐明这一机制将有助于提出一种以延长红细胞寿命为核心的新型肾性贫血治疗方法。

Abstract

Human erythrocytes retain phosphatidylserine (PS) only in the inner leaflet of plasma membranes during their 120-day lifespan to enforce membrane strengthen through associations with cytoskeletal proteins. Meanwhile, PS is exposed to the outer leaflet at the end of the lifespan for removal by phagocytosis of splenic macrophages. Consequently, their lifespan is determined by the localization of PS. PS-flippase activity of erythrocytes from an ATP11C-deficient patient was reduced by 90%, however, PS was unexposed in almost all erythrocytes from the patient. This suggests that flippase-independent mechanisms may retain PS in the inner leaflet. Depletion of cholesterol from erythrocyte membranes significantly facilitated PS exposure under low intracellular Ca condition, indicating that cholesterol may block the lipid scrambling. In senescent erythrocytes, ATP11C level and the intracellular ATP and K concentrations were decreased in turn to reduce the flippase activity. The senescent erythrocytes easily exposed PS by raising a subtle amount of intracellular Ca compared to young erythrocytes, indicating that the elevated intracellular Ca concentration is a critical determinant of erythrocyte lifespan. We also assessed the erythrocytes from patients with renal anemia: the shortened lifespan of erythrocytes. We found that ATP11C expression level and the intracellular K concentration were decreased in the anemic erythrocytes, indicating that the early onset of aging is triggered by the PS exposure. Elucidating this mechanism would propose a novel treatment focused on extending erythrocyte's lifespan for renal anemia.

如何引用

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