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Cell Rep. 2016 Jul 12;16(2):583-595. doi: 10.1016/j.celrep.2016.05.096. Epub 2016 Jun 30.

NeuCode Proteomics Reveals Bap1 Regulation of Metabolism.

Author information

1
Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
2
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
3
Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
4
Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
5
Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA.
6
Department of Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
7
Department of Safety Assessment, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
8
Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
9
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
10
Department of Transgenic Technology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
11
Department of Laboratory Animal Resources, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
12
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: jcoon@chem.wisc.edu.
13
Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: kirkpatrick.donald@gene.com.
14
Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: dey.anwesha@gene.com.

Abstract

We introduce neutron-encoded (NeuCode) amino acid labeling of mice as a strategy for multiplexed proteomic analysis in vivo. Using NeuCode, we characterize an inducible knockout mouse model of Bap1, a tumor suppressor and deubiquitinase whose in vivo roles outside of cancer are not well established. NeuCode proteomics revealed altered metabolic pathways following Bap1 deletion, including profound elevation of cholesterol biosynthetic machinery coincident with reduced expression of gluconeogenic and lipid homeostasis proteins in liver. Bap1 loss increased pancreatitis biomarkers and reduced expression of mitochondrial proteins. These alterations accompany a metabolic remodeling with hypoglycemia, hypercholesterolemia, hepatic lipid loss, and acinar cell degeneration. Liver-specific Bap1 null mice present with fully penetrant perinatal lethality, severe hypoglycemia, and hepatic lipid deficiency. This work reveals Bap1 as a metabolic regulator in liver and pancreas, and it establishes NeuCode as a reliable proteomic method for deciphering in vivo biology.

PMID:
27373151
PMCID:
PMC5546211
DOI:
10.1016/j.celrep.2016.05.096
[Indexed for MEDLINE]
Free PMC Article

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