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Integrating phosphoproteome and transcriptome reveals new determinants of macrophage multinucleation

Title: Integrating phosphoproteome and transcriptome reveals new determinants of macrophage multinucleation
Authors: Rotival, M
Ko, J-H
Srivastava, PK
Kerloc'h, A
Montoya, A
Mauro, C
Faull, P
Cutillas, PR
Petretto, E
Behmoaras, J
Item Type: Journal Article
Abstract: Macrophage multinucleation (MM) is essential for various biological processes such as osteoclast-mediated bone resorption and multinucleated giant cell-associated inflammatory reactions. Here we study the molecular pathways underlying multinucleation in the rat through an integrative approach combining MS-based quantitative phosphoproteomics (LC-MS/MS) and transcriptome (high-throughput RNA-sequencing) to identify new regulators of MM. We show that a strong metabolic shift toward HIF1-mediated glycolysis occurs at transcriptomic level during MM, together with modifications in phosphorylation of over 50 proteins including several ARF GTPase activators and polyphosphate inositol phosphatases. We use shortest-path analysis to link differential phosphorylation with the transcriptomic reprogramming of macrophages and identify LRRFIP1, SMARCA4, and DNMT1 as novel regulators of MM. We experimentally validate these predictions by showing that knock-down of these latter reduce macrophage multinucleation. These results provide a new framework for the combined analysis of transcriptional and post-translational changes during macrophage multinucleation, prioritizing essential genes, and revealing the sequential events leading to the multinucleation of macrophages.
Issue Date: 1-Mar-2015
Date of Acceptance: 9-Dec-2014
URI: http://hdl.handle.net/10044/1/57234
DOI: https://dx.doi.org/10.1074/mcp.M114.043836
ISSN: 1535-9476
Publisher: American Society for Biochemistry and Molecular Biology
Start Page: 484
End Page: 498
Journal / Book Title: Molecular and Cellular Proteomics
Volume: 14
Issue: 3
Copyright Statement: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: MR/M004716/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemical Research Methods
Biochemistry & Molecular Biology
SMALL-CELL CARCINOMA
OSTEOCLAST DIFFERENTIATION
HYPERCALCEMIC TYPE
SMARCA4 MUTATIONS
FUSION
ACTIVATION
GLOMERULONEPHRITIS
PROTEOMICS
HYPOXIA
OVARY
Animals
Cell Nucleus
Cells, Cultured
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNA Helicases
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Macrophages
Nuclear Proteins
Phosphorylation
Proteome
RNA-Binding Proteins
Rats
Rats, Inbred Lew
Rats, Inbred WKY
Sequence Analysis, RNA
Transcription Factors
DNA (Cytosine-5-)-Methyltransferase
MD Multidisciplinary
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Department of Medicine
Faculty of Medicine



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