Inverse Data-Driven Modeling and Multiomics Analysis Reveals Phgdh as a Metabolic Checkpoint of Macrophage Polarization and Proliferation.
Animals
Cell Polarity
/ drug effects
Cell Proliferation
/ drug effects
Gene Expression Regulation, Enzymologic
/ drug effects
Genomics
Glutamic Acid
/ metabolism
Glycine
/ metabolism
Interleukin-4
/ pharmacology
Ketoglutaric Acids
/ metabolism
Kinetics
Macrophages
/ cytology
Mechanistic Target of Rapamycin Complex 1
/ metabolism
Mice, Inbred C57BL
Models, Biological
Phosphoglycerate Dehydrogenase
/ genetics
Principal Component Analysis
Serine
/ metabolism
Tuberous Sclerosis Complex 2 Protein
/ metabolism
Phgdh
Tsc2
biochemical Jacobian
cancer
mTOR
macrophage polarization
macrophage proliferation
metabolic modeling
metabolomics
serine/glycine pathway
tumor-associated macrophages
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
04 02 2020
04 02 2020
Historique:
received:
24
11
2018
revised:
23
07
2019
accepted:
02
01
2020
entrez:
6
2
2020
pubmed:
6
2
2020
medline:
17
3
2021
Statut:
ppublish
Résumé
Mechanistic or mammalian target of rapamycin complex 1 (mTORC1) is an important regulator of effector functions, proliferation, and cellular metabolism in macrophages. The biochemical processes that are controlled by mTORC1 are still being defined. Here, we demonstrate that integrative multiomics in conjunction with a data-driven inverse modeling approach, termed COVRECON, identifies a biochemical node that influences overall metabolic profiles and reactions of mTORC1-dependent macrophage metabolism. Using a combined approach of metabolomics, proteomics, mRNA expression analysis, and enzymatic activity measurements, we demonstrate that Tsc2, a negative regulator of mTORC1 signaling, critically influences the cellular activity of macrophages by regulating the enzyme phosphoglycerate dehydrogenase (Phgdh) in an mTORC1-dependent manner. More generally, while lipopolysaccharide (LPS)-stimulated macrophages repress Phgdh activity, IL-4-stimulated macrophages increase the activity of the enzyme required for the expression of key anti-inflammatory molecules and macrophage proliferation. Thus, we identify Phgdh as a metabolic checkpoint of M2 macrophages.
Identifiants
pubmed: 32023468
pii: S2211-1247(20)30020-6
doi: 10.1016/j.celrep.2020.01.011
pmc: PMC7003064
pii:
doi:
Substances chimiques
Ketoglutaric Acids
0
Tuberous Sclerosis Complex 2 Protein
0
Interleukin-4
207137-56-2
Glutamic Acid
3KX376GY7L
Serine
452VLY9402
Phosphoglycerate Dehydrogenase
EC 1.1.1.95
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Glycine
TE7660XO1C
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1542-1552.e7Subventions
Organisme : Austrian Science Fund FWF
ID : P 27701
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : P 30857
Pays : Austria
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interest.
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