1. Large-Scale Quantitative Proteomics Identifies the Ubiquitin Ligase Nedd4-1 as an Essential Regulator of Liver Regeneration.
- Author
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Bachofner M, Speicher T, Bogorad RL, Muzumdar S, Derrer CP, Hürlimann F, Böhm F, Nanni P, Kockmann T, Kachaylo E, Meyer M, Padrissa-Altés S, Graf R, Anderson DG, Koteliansky V, Auf dem Keller U, and Werner S
- Subjects
- Animals, Endocytosis drug effects, ErbB Receptors metabolism, Gene Knockdown Techniques, Hepatocytes drug effects, Hepatocytes metabolism, Liver drug effects, Liver injuries, Liver metabolism, Liver pathology, Male, Mice, Inbred C57BL, Mitogens pharmacology, Nedd4 Ubiquitin Protein Ligases, Polyubiquitin metabolism, Proteome metabolism, RNA, Small Interfering metabolism, Reproducibility of Results, Signal Transduction drug effects, Ubiquitination drug effects, Endosomal Sorting Complexes Required for Transport metabolism, Liver Regeneration drug effects, Proteomics methods, Ubiquitin-Protein Ligases metabolism
- Abstract
The liver is the only organ in mammals that fully regenerates even after major injury. To identify orchestrators of this regenerative response, we performed quantitative large-scale proteomics analysis of cytoplasmic and nuclear fractions from normal versus regenerating mouse liver. Proteins of the ubiquitin-proteasome pathway were rapidly upregulated after two-third hepatectomy, with the ubiquitin ligase Nedd4-1 being a top hit. In vivo knockdown of Nedd4-1 in hepatocytes through nanoparticle-mediated delivery of small interfering RNA caused severe liver damage and inhibition of cell proliferation after hepatectomy, resulting in liver failure. Mechanistically, we demonstrate that Nedd4-1 is required for efficient internalization of major growth factor receptors involved in liver regeneration and their downstream mitogenic signaling. These results highlight the power of large-scale proteomics to identify key players in liver regeneration and the importance of posttranslational regulation of growth factor signaling in this process. Finally, they identify an essential function of Nedd4-1 in tissue repair., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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