PXD010657

PXD010657 is an original dataset announced via ProteomeXchange.

Title	Inverse data-driven modelling and multiomics analysis reveals PHGDH as a metabolic signature of M2 macrophages
Description	Activation of immune cells is accompanied by a metabolic reconfiguration of their cellular energy metabolism including shifts in glycolysis and mitochondrial respiration that critically regulate functional effector responses. However, while current mass spectrometry strategies identify overall or flux-dependent metabolite profiles of cells or tissues, they fail to comprehensively identify the checkpoint nodes and enzymes that are responsible for different metabolic outputs. Here, we demonstrate that a data-driven inverse modelling approach from mass spectrometry metabolomics data can be used to identify a causal biochemical node that influence overall metabolic profiles and reactions. In our study we applied this strategy to TSC2/mTORC1-dependent macrophage polarization. Using multiomics metabolomics, proteomics and transcriptomics analysis as well as enzymatic activity measurements we demonstrate that TSC2, a negative regulator of mTORC1 signaling, critically influences the cellular metabolism of macrophages by regulating the enzyme phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme that diverts carbon from glycolysis for de novo serine/glycine biosynthesis. This is the first evidence that the metabolic kinase mTORC1 positively regulates PHGDH activity in macrophages. Importantly, PHGDH itself is a central regulator of macrophage polarization. Anti-inflammatory (M2) macrophages have high PHGDH activity that is required for the expression of typical anti-inflammatory molecules. Inhibition of PHGDH activity suppressed marker genes in IL-4 stimulated M2 macrophages. This identifies PHGDH as a metabolic signature of M2 macrophages. The presented concept of data-driven inverse modelling and multiomics analysis allows for the systematic integration of genome-scale metabolic reconstruction, prediction and analysis of causal biochemical regulation.
HostingRepository	PRIDE
AnnounceDate	2020-05-26
AnnouncementXML	Submission_2020-05-26_11:59:23.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Wolfram Weckwerth
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2018-08-02 00:12:33	ID requested
⏵ 1	2020-05-26 11:59:24	announced

Wilson JL, N, ä, gele T, Linke M, Demel F, Fritsch SD, Mayr HK, Cai Z, Katholnig K, Sun X, Fragner L, Miller A, Haschemi A, Popa A, Bergthaler A, Hengstschl, ä, ger M, Weichhart T, Weckwerth W, Inverse Data-Driven Modeling and Multiomics Analysis Reveals Phgdh as a Metabolic Checkpoint of Macrophage Polarization and Proliferation. Cell Rep, 30(5):1542-1552.e7(2020) [pubmed]

curator keyword: Biological

submitter keyword: TSC2, TOR, Serin pathway, Macrophages, metabolomics, metabolic modelling, biochemical Jacobian,

Wolfram Weckwerth
contact affiliation	Department of Ecogenomics and Systems Biology, Division Molecular Systems Biology, University of Vienna, Austria
contact email	wolfram.weckwerth@univie.ac.at
lab head
Wolfram Weckwerth
contact affiliation	University of Vienna
contact email	wolfram.weckwerth@univie.ac.at
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/05/PXD010657

PRIDE project URI

• PRIDE
  1. PXD010657
     1. Label: PRIDE project
     2. Name: Inverse data-driven modelling and multiomics analysis reveals PHGDH as a metabolic signature of M2 macrophages