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Dev Cell. 2017 Sep 25;42(6):616-625.e8. doi: 10.1016/j.devcel.2017.07.025. Epub 2017 Sep 7.

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

Author information

1
Department of Biology, Institute of Molecular Health Sciences, ETH Zürich, 8093 Zürich, Switzerland.
2
David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Functional Genomics Center Zürich, University of Zürich/ETH Zürich, 8057 Zürich, Switzerland.
4
Department of Biology, Institute of Molecular Health Sciences, ETH Zürich, 8093 Zürich, Switzerland; Functional Genomics Center Zürich, University of Zürich/ETH Zürich, 8057 Zürich, Switzerland.
5
Swiss HPB Center, Division of Visceral and Transplantation Surgery, University Hospital Zürich, 8091 Zürich, Switzerland.
6
David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Health Science Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
Skolkovo Institute of Science and Technology, ul. Novaya, d.100, Skolkovo 143025, Russian Federation.
8
Department of Biology, Institute of Molecular Health Sciences, ETH Zürich, 8093 Zürich, Switzerland. Electronic address: ulrich.aufdemkeller@biol.ethz.ch.
9
Department of Biology, Institute of Molecular Health Sciences, ETH Zürich, 8093 Zürich, Switzerland. Electronic address: sabine.werner@biol.ethz.ch.

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.

KEYWORDS:

EGF; Eps15; HGF; Nedd4-1; hepatocyte; liver regeneration; proteomics; siRNA; ubiquitin

PMID:
28890072
DOI:
10.1016/j.devcel.2017.07.025
[Indexed for MEDLINE]
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