AGE-RAGE signal generates a specific NF-κB RelA "barcode" that directs collagen I expression.
AGE-RAGE signal generates a specific NF-κB RelA "barcode" that directs collagen I expression.
复制标题
AGE-RAGE 信号生成特定的 NF-κB RelA“条形码”，指导 I 型胶原蛋白的表达。
DOI：
10.1038/srep18822
复制
发表时间：
2016-01-05
影响因子：
4.6
通讯作者：
Lin L
中科院分区：
文献类型：
--
作者：
Peng Y;Kim JM;Park HS;Yang A;Islam C;Lakatta EG;Lin L
晚期糖基化终产物（AGEs）是糖修饰的生物分子，其随着年龄的增长而在体内积累，并且与多种年龄相关的结构和功能异常和疾病的发展有关。已经充分证明AGEs通过它们的受体介导信号传导以激活包括NF-κB在内的几种细胞程序，导致炎症。大量的刺激可以激活NF-κB;然而不同的刺激，或者在不同的细胞环境中对NF-κB的相同刺激，产生非常不同的转录景观和生理结果。NF-κB条形码假说假定细胞网络动力学产生信号特异性翻译后修饰，或NF-κB的“条形码”，并且签名“条形码”介导特定的基因表达模式。在目前的研究中，我们确定AGE-β信号转导导致NF-κB活化，从而指导胶原Ia 1和Ia 2的表达。我们进一步证明，AGE-E2信号诱导RelA在三个特定残基T254、S311和S536处磷酸化。这些修饰是I型胶原基因转录所必需的，是细胞网络动力学的结果。胶原蛋白含量的增加是动脉老化的标志，我们的工作提供了一个潜在的机制之间的联系，信号转导，NF-κB激活，和老化相关的动脉结构和功能的改变。
Advanced glycation end products (AGEs) are sugar-modified biomolecules that accumulate in the body with advancing age, and are implicated in the development of multiple age-associated structural and functional abnormities and diseases. It has been well documented that AGEs signal via their receptor RAGE to activate several cellular programs including NF-κB, leading to inflammation. A large number of stimuli can activate NF-κB; yet different stimuli, or the same stimulus for NF-κB in different cellular settings, produce a very different transcriptional landscape and physiological outcome. The NF-κB barcode hypothesis posits that cellular network dynamics generate signal-specific post-translational modifications, or a “barcode” to NF-κB, and that a signature “barcode” mediates a specific gene expression pattern. In the current study, we established that AGE-RAGE signaling results in NF-κB activation that directs collagen Ia1 and Ia2 expression. We further demonstrated that AGE-RAGE signal induces phosphorylation of RelA at three specific residues, T254, S311, and S536. These modifications are required for transcription of collagen I genes and are a consequence of cellular network dynamics. The increase of collagen content is a hallmark of arterial aging, and our work provides a potential mechanistic link between RAGE signaling, NF-κB activation, and aging-associated arterial alterations in structure and function.