Cell Reports
(Jul 2016)
NeuCode Proteomics Reveals Bap1 Regulation of Metabolism
Joshua M. Baughman,
Christopher M. Rose,
Ganesh Kolumam,
Joshua D. Webster,
Emily M. Wilkerson,
Anna E. Merrill,
Timothy W. Rhoads,
Rajkumar Noubade,
Paula Katavolos,
Justin Lesch,
Donald S. Stapleton,
Mary E. Rabaglia,
Kathy L. Schueler,
Raymond Asuncion,
Melanie Domeyer,
Jose Zavala-Solorio,
Michael Reich,
Jason DeVoss,
Mark P. Keller,
Alan D. Attie,
Alexander S. Hebert,
Michael S. Westphall,
Joshua J. Coon,
Donald S. Kirkpatrick,
Anwesha Dey
Affiliations
Joshua M. Baughman
Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Christopher M. Rose
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Ganesh Kolumam
Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Joshua D. Webster
Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Emily M. Wilkerson
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Anna E. Merrill
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Timothy W. Rhoads
Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA
Rajkumar Noubade
Department of Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Paula Katavolos
Department of Safety Assessment, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Justin Lesch
Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Donald S. Stapleton
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Mary E. Rabaglia
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Kathy L. Schueler
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Raymond Asuncion
Department of Transgenic Technology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Melanie Domeyer
Department of Transgenic Technology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Jose Zavala-Solorio
Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Michael Reich
Department of Laboratory Animal Resources, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Jason DeVoss
Department of Translational Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Mark P. Keller
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Alan D. Attie
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Alexander S. Hebert
Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA
Michael S. Westphall
Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA
Joshua J. Coon
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
Donald S. Kirkpatrick
Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
Anwesha Dey
Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
DOI
https://doi.org/10.1016/j.celrep.2016.05.096
Journal volume & issue
Vol. 16,
no. 2
Abstract
Read online
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.
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