Redox Regulation of PPARγ in Polarized Macrophages

PPAR Research
Verena TrümperAndreas von Knethen

Abstract

The peroxisome proliferator-activated receptor (PPARγ) is a central mediator of cellular lipid metabolism and immune cell responses during inflammation. This is facilitated by its role as a transcription factor as well as a DNA-independent protein interaction partner. We addressed how the cellular redox milieu in the cytosol and the nucleus of lipopolysaccharide (LPS)/interferon-γ- (IFNγ-) and interleukin-4- (IL4-) polarized macrophages (MΦ) initiates posttranslational modifications of PPARγ, that in turn alter its protein function. Using the redox-sensitive GFP2 (roGFP2), we validated oxidizing and reducing conditions following classical and alternative activation of MΦ, while the redox status of PPARγ was determined via mass spectrometry. Cysteine residues located in the zinc finger regions (amino acid fragments AA 90-115, AA 116-130, and AA 160-167) of PPARγ were highly oxidized, accompanied by phosphorylation of serine 82 in response to LPS/IFNγ, whereas IL4-stimulation provoked minor serine 82 phosphorylation and less cysteine oxidation, favoring a reductive milieu. Mutating these cysteines to alanine to mimic a redox modification decreased PPARγ-dependent reporter gene transactivation supporting a functional shift of PPAR...Continue Reading

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Citations

Jun 26, 2021·Drug Design, Development and Therapy·Jingjing LiJianye Wu
Aug 11, 2021·Journal of Experimental & Clinical Cancer Research : CR·Yuanyuan ZhengChuanyong Guo

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Methods Mentioned

BETA
protein folding
transfection
coimmunoprecipitation
protein assay
electrophoresis

Software Mentioned

FACS
FlowJo
Image Studio Digits

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