极化巨噬细胞中PPARγ的氧化还原调控。

IF 3.5 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL PPAR Research Pub Date : 2020-07-01 eCollection Date: 2020-01-01 DOI:10.1155/2020/8253831
Verena Trümper, Ilka Wittig, Juliana Heidler, Florian Richter, Bernhard Brüne, Andreas von Knethen
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引用次数: 9

摘要

过氧化物酶体增殖物激活受体(PPARγ)是炎症期间细胞脂质代谢和免疫细胞反应的中心介质。这是由其作为转录因子以及dna独立的蛋白质相互作用伙伴的作用促进的。我们研究了胞浆中的细胞氧化还原环境和脂多糖(LPS)/干扰素-γ- (IFNγ-)和白细胞介素-4- (IL4-)极化巨噬细胞的细胞核(MΦ)如何启动PPARγ的翻译后修饰,从而改变其蛋白质功能。使用氧化还原敏感的GFP2 (roGFP2),我们验证了经典和替代MΦ激活后的氧化和还原条件,同时通过质谱法确定PPARγ的氧化还原状态。PPARγ锌指区的半胱氨酸残基(氨基酸片段AA 90-115、AA 116-130和AA 160-167)在LPS/IFNγ的作用下被高度氧化,并伴随着丝氨酸82的磷酸化,而il4刺激引起丝氨酸82的轻微磷酸化和较少的半胱氨酸氧化,有利于还原环境。将这些半胱氨酸突变为丙氨酸以模拟氧化还原修饰,减少PPARγ依赖性报告基因的转激活,支持与MΦ表型相关的PPARγ的功能转移。这些数据表明,基于MΦ的氧化还原状态,调节PPARγ功能的不同机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Redox Regulation of PPARγ in Polarized Macrophages.

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 PPARγ associated with the MΦ phenotype. These data suggest distinct mechanisms for regulating PPARγ function based on the redox state of MΦ.

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来源期刊
PPAR Research
PPAR Research MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.20
自引率
3.40%
发文量
17
审稿时长
12 months
期刊介绍: PPAR Research is a peer-reviewed, Open Access journal that publishes original research and review articles on advances in basic research focusing on mechanisms involved in the activation of peroxisome proliferator-activated receptors (PPARs), as well as their role in the regulation of cellular differentiation, development, energy homeostasis and metabolic function. The journal also welcomes preclinical and clinical trials of drugs that can modulate PPAR activity, with a view to treating chronic diseases and disorders such as dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, and obesity.
期刊最新文献
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