Bile Acids Modulate Signaling by Functional Perturbation of Plasma Membrane Domains
Bile Acids Modulate Signaling by Functional Perturbation of Plasma Membrane Domains
复制标题
DOI：
10.1074/jbc.m113.519116
复制
发表时间：
2013-12-13
影响因子：
4.8
通讯作者：
Levental, Ilya
中科院分区：
文献类型：
--
作者：
Zhou, Yong;Maxwell, Kelsey N.;Levental, Ilya
背景：胆汁酸（BA）影响细胞膜。结果：BA稳定了质膜结构域，导致膜蛋白重组和信号扰动。结论：BAs通过调节细胞膜纳米结构域的稳定性影响细胞功能。重要性：这些结果表明，功能性膜结构域和非受体介导的BA signaling.Eukaryotic细胞膜的调节机制被组织成功能性脂质和蛋白质结构域，最广泛的研究是膜筏。虽然筏已与许多质膜功能，这些领域本身的调节机制仍然不明确。胆汁酸（BA），其主要功能是溶解膳食脂质用于消化和吸收，可以通过直接与膜相互作用来影响细胞。为了研究这些相互作用是否会影响生物膜中的结构域组织，我们测定了BA对仿生合成脂质体、离体质膜和活细胞的影响。在细胞毒性浓度下，BA溶解合成膜和细胞衍生膜，破坏活细胞质膜，暗示质膜损伤是BA细胞毒性的机制。在亚毒性浓度下，BA显着稳定巨质膜囊泡中的结构域分离，而不影响共存结构域之间的蛋白质分配。结构域稳定化是BA结合到非筏结构域并使其无序化的结果，从而通过增强结构域的不相容性来促进分离。与在合成和分离的生物膜中观察到的物理变化一致，BA重组了完整的细胞膜，如通过膜锚定的Ras亚型的空间分布所评价的。K-Ras的纳米簇，相关的非筏膜结构域，在完整的质膜增强，而组织的H-Ras不受影响。BA诱导的Ras侧向分离的变化通过MAPK增强EGF诱导的信号传导，证实了BA通过改变质膜的物理性质来影响细胞信号转导的能力。这些观察结果表明，一般的，膜介导的机制，生物两亲物可以产生细胞的影响。
Background: Bile acids (BAs) affect cellular membranes. Results: BAs stabilize domains in plasma membranes, leading to reorganization of membrane proteins and signaling perturbations. Conclusion: BAs affect cell function by modulating the stability of plasma membrane nanodomains. Significance: These results suggest mechanisms for regulation of functional membrane domains and nonreceptor-mediated BA signaling.Eukaryotic cell membranes are organized into functional lipid and protein domains, the most widely studied being membrane rafts. Although rafts have been associated with numerous plasma membrane functions, the mechanisms by which these domains themselves are regulated remain undefined. Bile acids (BAs), whose primary function is the solubilization of dietary lipids for digestion and absorption, can affect cells by interacting directly with membranes. To investigate whether these interactions affected domain organization in biological membranes, we assayed the effects of BAs on biomimetic synthetic liposomes, isolated plasma membranes, and live cells. At cytotoxic concentrations, BAs dissolved synthetic and cell-derived membranes and disrupted live cell plasma membranes, implicating plasma membrane damage as the mechanism for BA cellular toxicity. At subtoxic concentrations, BAs dramatically stabilized domain separation in Giant Plasma Membrane Vesicles without affecting protein partitioning between coexisting domains. Domain stabilization was the result of BA binding to and disordering the nonraft domain, thus promoting separation by enhancing domain immiscibility. Consistent with the physical changes observed in synthetic and isolated biological membranes, BAs reorganized intact cell membranes, as evaluated by the spatial distribution of membrane-anchored Ras isoforms. Nanoclustering of K-Ras, related to nonraft membrane domains, was enhanced in intact plasma membranes, whereas the organization of H-Ras was unaffected. BA-induced changes in Ras lateral segregation potentiated EGF-induced signaling through MAPK, confirming the ability of BAs to influence cell signal transduction by altering the physical properties of the plasma membrane. These observations suggest general, membrane-mediated mechanisms by which biological amphiphiles can produce their cellular effects.