AGE-RAGE signal generates a specific NF-κB RelA “barcode” that directs collagen I expression

• Published in: Scientific reports 2016-01, Vol.6 (1), p.18822-18822, Article 18822
• Main Authors: Peng, Yunqian, Kim, Ji-Min, Park, Hal-Sol, Yang, Annie, Islam, Celia, Lakatta, Edward G., Lin, Li
• Format: Article
• Language: English
• Subjects: 13/51; 13/95; 38; 38/70; 631/80/458/1733; 692/4017; 82/80; Animals; Chromatin Immunoprecipitation; Collagen Type I - genetics; Fibroblasts; Gene Expression Regulation; Gene Knockout Techniques; Glycation End Products, Advanced - metabolism; High-Throughput Nucleotide Sequencing; Humanities and Social Sciences; Macrophages - metabolism; MAP Kinase Signaling System; Mice; multidisciplinary; Mutation; Protein Binding; Protein Processing, Post-Translational; Receptor for Advanced Glycation End Products - metabolism; Regulatory Sequences, Nucleic Acid; Science; Signal Transduction; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Transcription, Genetic
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep18822

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.