Inverse Data-Driven Modeling and Multiomics Analysis Reveals Phgdh as a Metabolic Checkpoint of Macrophage Polarization and Proliferation

Author(s)
Jayne Louise Wilson, Thomas Naegele, Monika Linke, Florian Demel, Stephanie D. Fritsch, Hannah Katharina Mayr, Zhengnan Cai, Karl Katholnig, Xiaoliang Sun, Lena Fragner, Anne Miller, Arvand Haschemi, Alexandra Popa, Andreas Bergthaler, Markus Hengstschlaeger, Thomas Weichhart, Wolfram Weckwerth
Abstract

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.

Organisation(s)
Research Platform Vienna Metabolomics Center, Functional and Evolutionary Ecology, Large-Instrument Facility for Mass Spectrometry in Life Sciences
External organisation(s)
Medizinische Universität Wien, Österreichische Akademie der Wissenschaften (ÖAW), Ludwig-Maximilians-Universität München, Universität Wien
Journal
Cell Reports
Volume
30
Pages
1542-1552
ISSN
2211-1247
DOI
https://doi.org/10.1016/j.celrep.2020.01.011
Publication date
02-2020
Peer reviewed
Yes
Austrian Fields of Science 2012
101028 Mathematical modelling, 106044 Systems biology, 106002 Biochemistry, 106052 Cell biology
Keywords
Portal url
https://ucris.univie.ac.at/portal/en/publications/inverse-datadriven-modeling-and-multiomics-analysis-reveals-phgdh-as-a-metabolic-checkpoint-of-macrophage-polarization-and-proliferation(8453632d-b7f0-43fe-8994-c44a676803b5).html