期刊
JOURNAL OF PROTEOME RESEARCH
卷 9, 期 7, 页码 3465-3478出版社
AMER CHEMICAL SOC
DOI: 10.1021/pr9011377
关键词
Amino acid-coded mass tagging; immune response; LC-MS/MS; tumor necrosis factor-alpha; 14-3-3 epsilon; nuclear factor-kappa B; TAK1; PPM1B
资金
- Shanghai Science and Technology Development [03DZ14024, 07ZR14010]
- 863 High Technology Foundation of China [2006AA02A310]
- U.S. NIH [1 R01AI064806-01A2]
- U.S. Department of Energy, the Office of Science (BER) [DE-FG02-07ER64422]
Inflammation is tightly regulated by nuclear factor-kappa B (NF-kappa B), and if left unchecked excessive NF-kappa B activation for cytokine overproduction can lead to various pathogenic consequences including carcinogenesis. A proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), can be used to explore possible mechanisms whereby unknown functional pathways modulate the NF-kappa B activity for regulating TNF-a alpha-induced inflammation. Given the multifunctional nature of 14-3-3 family proteins and the recent finding of their presence in the TNF-oJNF-KB pathway network, we used a dual-tagging quantitative proteomic method to first profile the TNF-a-inducible interacting partners of 14-3-3 E, the least characterized 14-3-3 isomer in the family. For the first time, we found that TNF-alpha stimulation enhances the interactions between 14-3-3 epsilon and some key components in the mitogen-activated protein kinase (MAPK) signal module which is located at the immediate upstream of NF-kappa B, including transforming growth factor-beta activated kinase-1 (TAK1) and its interacting protein, protein phosphatase 2C/3 (PPM1B). By using confocal laser scanning, we observed the TNF-alpha-induced colocalizations among 14-3-3 epsilon, TAK1, and protein phosphatase 2C/3 (PPM1B), and these interactions were also TNF-alpha-inducible in different cell types. Further, we found that during the full course of the cellular response to TNF-alpha, the interactions between 14-3-3 epsilon and these two proteins were dynamic and were closely correlated with the time course-dependent changes in NF-kappa B activity, suggesting that these 14-3-3 E. interactions are the critical points of convergence for TNF-alpha signaling for modulating NF-kappa B activity. We then postulated a mechanistic view describing how 14-3-3 r coordinates its dynamic interactions with TAK1 and PPM1B for differentially modulating TNF-alpha-induced changes in NF-kappa B activity. By using bioinformatics tools, we constructed the network involving most of the 14-3-3 epsilon interacting proteins identified in our proteomic study. We revealed that 14-3-3 epsilon coordinates the cross talks between the MAPK signal module and other molecular pathways/biological processes primarily including protein metabolism and synthesis, DNA repair, and cell cycle regulation where pharmacological targets for therapeutic intervention could be systematically located.
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