S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate

Qin, Wei; Qin, Ke; Zhang, Yanling; Jia, Wentong; Chen, Ying; Cheng, Bo; Peng, Linghang; Chen, Nan; Liu, Yuan; Zhou, Wen; Wang, Yanling; Chen, Xing; Wang, Chu

doi:10.1038/s41589-019-0323-5

Cited by 214 publications

(195 citation statements)

References 55 publications

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“…Interestingly, we observed cysteine itaconatylation of peptides corresponding to gamma-interferon-inducible lysosomal thiol reductase (Gilt) and protein disulfide-isomerase A3 (Pdia3), both of which regulate cellular thiol/disulfide redox balance. We also observed itaconatylation of Gapdh and Aldoa, similar to a recent study of thiol reactivity using chemical profiling (Qin et al 2019). While the +130.03 Da modified proteins can be explained by itaconate, we reasoned that the +146.02 Da modified peptides may be due to the modification by oxidized itaconate or oxidation of itaconatylated cysteine to sulfoxide, an oxidized +15.99…”

Section: Figsupporting

confidence: 90%

Discovery of protein modifications using high resolution differential mass spectrometry proteomics

Cifani¹,

Li²,

Luo³

et al. 2020

Preprint

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Recent studies have revealed diverse amino acid, post-translational and non-canonical modifications of proteins in diverse organisms and tissues. However, their unbiased detection and analysis remain hindered by technical limitations. Here, we present a spectral alignment method for the identification of protein modifications using highresolution mass spectrometry proteomics. Termed SAMPEI for Spectral Alignment-based Modified PEptide Identification, this open-source algorithm is designed for the discovery of functional protein and peptide signaling modifications, without prior knowledge of their identities. Using synthetic standards and controlled chemical labeling experiments, we demonstrate its high specificity and sensitivity for the discovery of sub-stoichiometric protein modifications in complex cellular extracts. SAMPEI mapping of mouse macrophage differentiation revealed diverse post-translational protein modifications, including distinct forms of cysteine itaconatylation. SAMPEI's robust parameterization and versatility are expected to facilitate the discovery of biological modifications of diverse macromolecules. SAMPEI is implemented as a Python package, and is available opensource from BioConda and GitHub (https://github.com/FenyoLab/SAMPEI).

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Section: Figsupporting

confidence: 90%

Discovery of protein modifications using high resolution differential mass spectrometry proteomics

Cifani¹,

Li²,

Luo³

et al. 2020

Preprint

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show abstract

“…Itaconate can also activate the anti-inflammatory cellular programming of nuclear factor erythroid 2-related factor 2 (Nrf2) via alkylation of cysteine residues on the protein KEAP1 [40]. Additionally, itaconate can inhibit LPS-induced IL-1β secretion by impairing glycolytic flux via targeting glycolytic enzymes GAPDH or fructose-bisphosphate aldolase A [41,42]. Collectively, these studies highlight the importance of the ETC and the cycling of the TCA cycle in the regulation of the NLRP3 inflammasome ( Figure 2).…”

Section: Oxidative Phosphorylation and Citric Acid Cycle Metabolitesmentioning

confidence: 99%

The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging

Meyers

Zhu

2020

Cells

123

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In response to inflammatory stimuli, immune cells reconfigure their metabolism and bioenergetics to generate energy and substrates for cell survival and to launch immune effector functions. As a critical component of the innate immune system, the nucleotide-binding and oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome can be activated by various endogenous and exogenous danger signals. Activation of this cytosolic multiprotein complex triggers the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and initiates pyroptosis, an inflammatory form of programmed cell death. The NLRP3 inflammasome fuels both chronic and acute inflammatory conditions and is critical in the emergence of inflammaging. Recent advances have highlighted that various metabolic pathways converge as potent regulators of the NLRP3 inflammasome. This review focuses on our current understanding of the metabolic regulation of the NLRP3 inflammasome activation, and the contribution of the NLRP3 inflammasome to inflammaging.

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“…inhibiting glycolytic enzymes aldolase A and glyceraldehyde-3-phosphate hydrogenase in RAW 264.7 macrophage cell lines (148,149). Itaconate has also been shown to inhibit succinate dehydrogenase, which might reprogram citric acid cycle function and facilitate mROS generation due to reverse electron transport secondary to inhibition of SDH-dependent complex II (150).…”

Section: Reprogramming Of Glycolysismentioning

confidence: 99%

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

et al. 2020

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Critically ill, severely injured and high-risk surgical patients are vulnerable to secondary infections during hospitalization and after hospital discharge. Studies show that the mitochondrial function and oxidative metabolism of monocytes and macrophages are impaired during sepsis. Alternatively, treatment with microbe-derived ligands, such as monophosphoryl lipid A (MPLA), peptidoglycan, or β-glucan, that interact with toll-like receptors and other pattern recognition receptors on leukocytes induces a state of innate immune memory that confers broad-spectrum resistance to infection with common hospital-acquired pathogens. Priming of macrophages with MPLA, CPG oligodeoxynucleotides (CpG ODN), or β-glucan induces a macrophage metabolic phenotype characterized by mitochondrial biogenesis and increased oxidative metabolism in parallel with increased glycolysis, cell size and granularity, augmented phagocytosis, heightened respiratory burst functions, and more effective killing of microbes. The mitochondrion is a bioenergetic organelle that not only contributes to energy supply, biosynthesis, and cellular redox functions but serves as a platform for regulating innate immunological functions such as production of reactive oxygen species (ROS) and regulatory intermediates. This review will define current knowledge of leukocyte metabolic dysfunction during and after sepsis and trauma. We will further discuss therapeutic strategies that target leukocyte mitochondrial function and might have value in preventing or reversing sepsis-and trauma-induced immune dysfunction.

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S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate

Cited by 214 publications

References 55 publications

Discovery of protein modifications using high resolution differential mass spectrometry proteomics

Discovery of protein modifications using high resolution differential mass spectrometry proteomics

The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

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