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Dynamic quantitative proteomics characterization of TNF-α-induced necroptosis

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Abstract

Emerging evidence suggested that necroptosis has essential functions in many human inflammatory diseases, but the molecular mechanisms of necroptosis remain unclear. Here, we employed SILAC quantitatively dynamic proteomics to compare the protein changes during TNF-α-induced necroptosis at different time points in murine fibrosarcoma L929 cells with caspase-8 deficiency, and then performed the systematical analysis on the signaling networks involved in the progress using bioinformatics methods. Our results showed that a total of 329, 421 and 378 differentially expressed proteins were detected at three stages of necroptosis, respectively. Gene ontology and ingenuity pathway analysis (IPA) revealed that the proteins regulated at early stages of necroptosis (2, 6 h) were mainly involved in mitochondria dysfunction, oxidative phosphorylation and Nrf-2 signaling, while the expression levels of the proteins related to ubiquitin, Nrf-2, and NF-κB pathways were found to have changes at last stages of necroptosis (6, 18 h). Taken together, we demonstrated for the first time that dysfunction of mitochondria and ubiquitin–proteasome signaling contributed to the initiation and execution of necroptosis. These findings may provide clues for the identification of important regulators in necroptosis and the development of novel therapeutic strategies for the related diseases.

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Acknowledgments

This work was supported by the National Basic Research Program “973” of China (2011CB910700 to Q.Y.H.).

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Authors and Affiliations

  1. Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China

    Yang Wang, Zhi-Hao Huang, Yang-Jia Li, Gui-Wei He, Ru-Yuan Yu, Jie Yang, Wan-Ting Liu, Bin Li & Qing-Yu He

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  1. Yang Wang
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  2. Zhi-Hao Huang
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Correspondence to Wan-Ting Liu, Bin Li or Qing-Yu He.

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Wang, Y., Huang, ZH., Li, YJ. et al. Dynamic quantitative proteomics characterization of TNF-α-induced necroptosis. Apoptosis 21, 1438–1446 (2016). https://doi.org/10.1007/s10495-016-1300-z

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  • DOI: https://doi.org/10.1007/s10495-016-1300-z

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