Large-Scale Quantitative Proteomics Identifies the Ubiquitin Ligase Nedd4-1 as an Essential Regulator of Liver Regeneration

• Published in: Developmental cell Vol. 42; no. 6; pp. 616 - 625.e8
• Main Authors: Bachofner, Marc, Speicher, Tobias, Bogorad, Roman L., Muzumdar, Sukalp, Derrer, Carina P., Hürlimann, Fabrizio, Böhm, Friederike, Nanni, Paolo, Kockmann, Tobias, Kachaylo, Ekaterina, Meyer, Michael, Padrissa-Altés, Susagna, Graf, Rolf, Anderson, Daniel G., Koteliansky, Victor, auf dem Keller, Ulrich, Werner, Sabine
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25-09-2017
• Subjects: Animals; EGF; Endocytosis - drug effects; Endosomal Sorting Complexes Required for Transport - metabolism; Eps15; Gene Knockdown Techniques; hepatocyte; Hepatocytes - drug effects; Hepatocytes - metabolism; HGF; Liver - drug effects; Liver - injuries; Liver - metabolism; Liver - pathology; liver regeneration; Liver Regeneration - drug effects; Male; Mice, Inbred C57BL; Mitogens - pharmacology; Nedd4 Ubiquitin Protein Ligases; Nedd4-1; Polyubiquitin - metabolism; Proteome - metabolism; proteomics; Proteomics - methods; Receptor, Epidermal Growth Factor - metabolism; Reproducibility of Results; RNA, Small Interfering - metabolism; Signal Transduction - drug effects; siRNA; ubiquitin; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - drug effects; hepatocyte; proteomics; EGF; HGF; siRNA; Eps15; liver regeneration; ubiquitin; Nedd4-1
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2017.07.025

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.
•Proteomics identified regulated proteins and pathways in the regenerating liver•The ubiquitin ligase Nedd4-1 is an essential regulator of liver regeneration•Nedd4-1 promotes growth factor receptor internalization and efficient signaling•Posttranslational regulation of growth factor signaling controls liver regeneration
Using large-scale quantitative proteomics, Bachofner, Speicher et al. identified the ubiquitin ligase Nedd4-1 as an essential regulator of liver regeneration. Nedd4-1 deficiency attenuated growth factor receptor internalization and signaling, demonstrating a crucial role of posttranslational modification of growth factor signaling in liver regeneration.