Cell signalling by reactive lipid species: new concepts and molecular mechanisms.
Cell signalling by reactive lipid species: new concepts and molecular mechanisms.
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DOI：
10.1042/bj20111752
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发表时间：
2012-03-15
期刊：
影响因子：
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通讯作者：
Darley-Usmar VM
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文献类型：
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作者：
Higdon A;Diers AR;Oh JY;Landar A;Darley-Usmar VM
脂质过氧化过程在生物学中广泛存在，并通过酶和非酶途径介导。相当大比例的氧化脂质产物本质上是亲电的，RLS（反应性脂质物种），并与细胞亲核试剂反应，如氨基酸半胱氨酸、赖氨酸和组氨酸。亲电试剂的细胞信号传导似乎仅限于对蛋白质中半胱氨酸残基的修饰，而非特异性毒性作用涉及对其他亲核试剂的修饰。研究发现，RLS参与了多种生理途径，包括通过修饰特定信号蛋白来解决炎症、细胞死亡和诱导细胞抗氧化剂。蛋白质的共价修饰赋予了这种信号机制一些独特的特征，我们称之为“共价优势”。例如，信号蛋白的共价修饰允许信号随时间积累。亲电试剂对细胞信号通路的激活是分层的，依赖于亲电试剂的内在化学反应性、它所暴露的胞内结构域和位阻因子等因素的复杂相互作用。这介绍了亲电信号域的概念，其中脂类亲电试剂的产生与含硫醇的信号蛋白非常接近。此外，我们提出谷胱甘肽和相关酶的作用是使信号域免受不受控制的亲电应激的影响。信号的持续性反过来又受到蛋白酶体途径的调节，蛋白酶体途径本身可能受到RLS的氧化还原调节。RLS介导的细胞死亡与生物能量功能障碍有关，受损蛋白可能通过溶酶体自噬途径被清除。
The process of lipid peroxidation is widespread in biology and is mediated through both enzymatic and non-enzymatic pathways. A significant proportion of the oxidized lipid products are electrophilic in nature, the RLS (reactive lipid species), and react with cellular nucleophiles such as the amino acids cysteine, lysine and histidine. Cell signalling by electrophiles appears to be limited to the modification of cysteine residues in proteins, whereas non-specific toxic effects involve modification of other nucleophiles. RLS have been found to participate in several physiological pathways including resolution of inflammation, cell death and induction of cellular antioxidants through the modification of specific signalling proteins. The covalent modification of proteins endows some unique features to this signalling mechanism which we have termed the ‘covalent advantage’. For example, covalent modification of signalling proteins allows for the accumulation of a signal over time. The activation of cell signalling pathways by electrophiles is hierarchical and depends on a complex interaction of factors such as the intrinsic chemical reactivity of the electrophile, the intracellular domain to which it is exposed and steric factors. This introduces the concept of electrophilic signalling domains in which the production of the lipid electrophile is in close proximity to the thiol-containing signalling protein. In addition, we propose that the role of glutathione and associated enzymes is to insulate the signalling domain from uncontrolled electrophilic stress. The persistence of the signal is in turn regulated by the proteasomal pathway which may itself be subject to redox regulation by RLS. Cell death mediated by RLS is associated with bioenergetic dysfunction, and the damaged proteins are probably removed by the lysosome-autophagy pathway.