Malonylation of GAPDH is an inflammatory signal in macrophages

Galván-Peña, Silvia; Carroll, Richard G.; Newman, Carla F.; Hinchy, Elizabeth C.; Pålsson-McDermott, Eva M.; Robinson, Elektra Kantzari; Covarrubias, Sergio; Nadin, Alan; James, Andrew M.; Haneklaus, Moritz; Carpenter, Susan; Kelly, Vincent P.; Murphy, Michael P.; Modis, Louise K.; O’Neill, Luke A.J.

doi:10.1038/s41467-018-08187-6

Cited by 133 publications

(94 citation statements)

References 56 publications

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“…For instance, a recent work documented that malonyl-CoA critically participated in macrophage activation via promoting the malonylation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Malonylation of GAPDH (K213) leads to its dissociation from TNF-α mRNA, promoting TNF-α translation in macrophages [116]. As thus, protein malonylation may also function in the immune system to participate in CVDs, and the enzymes regulating malonylation may be targeted for the treatment of CVDs.…”

Section: Malonate and Malonylationmentioning

confidence: 99%

Short-chain fatty acid, acylation and cardiovascular diseases

2020

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Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Metabolic dysfunction is a fundamental core mechanism underlying CVDs. Previous studies generally focused on the roles of long-chain fatty acids (LCFAs) in CVDs. However, a growing body of study has implied that short-chain fatty acids (SCFAs: namely propionate, malonate, butyrate, 2-hydroxyisobutyrate (2-HIBA), β-hydroxybutyrate, crotonate, succinate, and glutarate) and their cognate acylations (propionylation, malonylation, butyrylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, crotonylation, succinylation, and glutarylation) participate in CVDs. Here, we attempt to provide an overview landscape of the metabolic pattern of SCFAs in CVDs. Especially, we would focus on the SCFAs and newly identified acylations and their roles in CVDs, including atherosclerosis, hypertension, and heart failure. Clinical Science (2020) 134 657-676 https://doi.org/10.1042/CS20200128 cofactors in certain protein acylations, such as propionylation [14], malonylation [15], butyrylation [14], 2-hydroxyisobutyrylation [16], β-hydroxybutyrylation [17], crotonylation [18], succinylation [19], and glutarylation [20]. These discoveries give us a deeper understanding of PTM. Among PTMs, protein acetylation is the earliest discovered and most studied. Similar to protein acetylation, various studies have shown that these newly discovered PTMs are also involved in physiological and pathophysiological processes, including cardiovascular homeostasis.Here in this review, we will summarize SCFAs, protein acylations, and their emerging roles in CVDs, including atherosclerosis, hypertension, and heart failure. The metabolic pattern and FAs in CVDsThe heart is an 'omnivore' , using FAs, glucose, lactate, ketone bodies, and amino acids as metabolic substrates [5,6]. The substrates utilized by the embryonic heart are significantly different from those used by the adult heart. The embryonic heart depends primarily on glycolysis as well as lactate oxidation to produce energy [21]. The newborn and adult heart shift toward the remarkable utilization of FAs to meet cardiac energy demand [5,9]. In failing hearts, a decrease in FA oxidation and an increase in glycolysis are critically involved in cardiac dysfunction [22]. As thus, the metabolic pattern is essential for maintaining cardiac and vascular functions.Diabetes, hypertension, and obesity contribute to heart failure syndrome. Accumulating evidence suggests that hypertension, ischemic hearts, and heart failure induce a shift in substrate toward the remarkable utilization of glucose to generate energy. Despite this shift, the FA oxidation remains to make much energy for the diseased heart [23]. Since FAs are the predominant substrates for cardiomyocytes, alterations in FA metabolism have been implicated as causal in cardiac diseases. FAs within cells and in the circulation are critically involved in cardiometabolic diseases. CVDs are closely associated with lifestyle and metabolic status, which affect circul...

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Section: Malonate and Malonylationmentioning

confidence: 99%

Short-chain fatty acid, acylation and cardiovascular diseases

2020

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“…59 In a parallel fashion, Tnf mRNA is bound to GAPDH in resting macrophages, and LPS-stimulated GAPDH malonylation mediates both the release of the cytokine coding mRNA, thereby allowing translation, and simultaneously favors enhanced glycolysis to support subsequent steps in activation including the production of IL-1β. 60…”

Section: Post-translational Modifications Driven By Metabolismmentioning

confidence: 99%

Cell‐intrinsic metabolic regulation of mononuclear phagocyte activation: Findings from the tip of the iceberg

Bakker

Pearce

2020

Immunological Reviews

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We have only recently started to appreciate the extent to which immune cell activation involves significant changes in cellular metabolism. We are now beginning to understand how commitment to specific metabolic pathways influences aspects of cellular biology that are the more usual focus of immunological studies, such as activation-induced changes in gene transcription, post-transcriptional regulation of transcription, post-translational modifications of proteins, cytokine secretion, etc. Here, we focus on metabolic reprogramming in mononuclear phagocytes downstream of stimulation with inflammatory signals (such as LPS and IFNγ) vs alternative activation signals (IL-4), with an emphasis on work on dendritic cells and macrophages from our laboratory, and related studies from others. We cover aspects of glycolysis and its branching pathways (glycogen synthesis, pentose phosphate, serine synthesis, hexose synthesis, and glycerol 3 phosphate shuttle), the tricarboxylic acid pathway, fatty acid synthesis and oxidation, and mitochondrial biology. Although our understanding of the metabolism of mononuclear phagocytes has progressed significantly over the last 10 years, major challenges remain, including understanding the effects of tissue residence on metabolic programming related to cellular activation, and the translatability of findings from mouse to human biology. K E Y W O R D SThis is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…Previous reports showed that phosphorylation and glycation of GAPDH are involved in the regulation of (PPI) and intracellular localization of the enzyme, and that the aggregation of GAPDH can be affected by all types of PTMs (Muronetz et al, 2016). Lysine 213 of GAPDH can be malonylated in macrophages following lipopolysaccharide (LPS) stimulation, which causes its dissociation from several inflammatory mRNAs, promoting translation (Galván-Peña et al, 2019), implying that Kmal has important roles in these processes. A total of 83 malonylated proteins identified in the present study had also been identified as acetylated proteins in a previous study (Jeffers and Sullivan, 2012).…”

Section: Advanced Functional Enrichment Of Malonylated Proteinsmentioning

confidence: 99%

Global Proteomic Analysis of Lysine Malonylation in Toxoplasma gondii

Nie

Liang

et al. 2020

Front. Microbiol.

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Lysine malonylation (Kmal) is a new post-translational modification (PTM), which has been reported in several prokaryotic and eukaryotic species. Although Kmal can regulate many and diverse biological processes in various organisms, knowledge about this important PTM in the apicomplexan parasite Toxoplasma gondii is limited. In this study, we performed the first global profiling of malonylated proteins in T. gondii tachyzoites using affinity enrichment and Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Three experiments performed in tandem revealed 294, 345, 352 Kmal sites on 203, 236, 230 malonylated proteins, respectively. Computational analysis showed the identified malonylated proteins to be localized in various subcellular compartments and involved in many cellular functions, particularly mitochondrial function. Additionally, one conserved Kmal motif with a strong bias for cysteine was detected. Taken together, these findings provide the first report of Kmal profile in T. gondii and should be an important resource for studying the physiological roles of Kmal in this parasite.

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Malonylation of GAPDH is an inflammatory signal in macrophages

Cited by 133 publications

References 56 publications

Short-chain fatty acid, acylation and cardiovascular diseases

Short-chain fatty acid, acylation and cardiovascular diseases

Cell‐intrinsic metabolic regulation of mononuclear phagocyte activation: Findings from the tip of the iceberg

Global Proteomic Analysis of Lysine Malonylation in Toxoplasma gondii

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