An Expanding Repertoire of Protein Acylations

Xu, Yuxuan; Shi, Zhenyu; Bao, Li

doi:10.1016/j.mcpro.2022.100193

Cited by 44 publications

(43 citation statements)

References 168 publications

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“…Regulation of proteins by post-translational modifications (PTM) participates in adaptive reprogramming of metabolic fluxes. While epigenetic mechanisms involving acetylation of histones are long-known, lately also other types of acylation, and acylation of metabolic proteins have drawn increasing attention regarding metabolic regulation [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy

Zavileyskiy

Aleshin²,

Kaehne³

et al. 2022

IJMS

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Abnormal energy expenditure during seizures and metabolic regulation through post-translational protein acylation suggest acylation as a therapeutic target in epilepsy. Our goal is to characterize an interplay between the brain acylation system components and their changes after seizures. In a rat model of pentylenetetrazole (PTZ)-induced epilepsy, we quantify 43 acylations in 29 cerebral cortex proteins; levels of NAD+; expression of NAD+-dependent deacylases (SIRT2, SIRT3, SIRT5); activities of the acyl-CoA-producing/NAD+-utilizing complexes of 2-oxoacid dehydrogenases. Compared to the control group, acylations of 14 sites in 11 proteins are found to differ significantly after seizures, with six of the proteins involved in glycolysis and energy metabolism. Comparing the single and chronic seizures does not reveal significant differences in the acylations, pyruvate dehydrogenase activity, SIRT2 expression or NAD+. On the contrary, expression of SIRT3, SIRT5 and activity of 2-oxoglutarate dehydrogenase (OGDH) decrease in chronic seizures vs. a single seizure. Negative correlations between the protein succinylation/glutarylation and SIRT5 expression, and positive correlations between the protein acetylation and SIRT2 expression are shown. Our findings unravel involvement of SIRT5 and OGDH in metabolic adaptation to seizures through protein acylation, consistent with the known neuroprotective role of SIRT5 and contribution of OGDH to the Glu/GABA balance perturbed in epilepsy.

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Section: Introductionmentioning

confidence: 99%

The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy

Zavileyskiy

Aleshin²,

Kaehne³

et al. 2022

IJMS

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“…To further understand the metabolic impact of lysine acylation in syntrophs and other organisms, we should consider characterizing them in a comprehensive and unbiased manner. Mass spectrometry-based proteomics is a powerful tool for analyzing the acylome (Xu, Shi & Bao, 2022). Proteomics can identify the broad scope of PTMs occurring within a biological system, but analyzing a wide range of acylations can present analytical challenges such as potential sequence misidentifications (Lee et al, 2013; Kim, Zhong & Pandey, 2016).…”

Section: Discussionmentioning

confidence: 99%

Dynamic acylome reveals metabolite driven modifications in Syntrophomonas wolfei

Muroski

Arbing

et al. 2022

Preprint

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Syntrophomonas wolfei is an anaerobic syntrophic microbe that degrades short-chain fatty acids to acetate, hydrogen, and/or formate. This thermodynamically unfavorable process proceeds through a series of reactive acyl-Coenzyme A species (RACS). In other prokaryotic and eukaryotic systems, the production of intrinsically reactive metabolites correlates with acyl-lysine modifications, which have been shown to play a significant role in metabolic processes. Analogous studies with syntrophic bacteria, however, are relatively unexplored and we hypothesize that highly abundant acylations could exist in S. wolfei proteins, corresponding to the RACS derived from degrading fatty acids. Here, by mass spectrometry-based proteomics (LC-MS/MS), we characterize and compare acylome profiles of two S. wolfei subspecies grown on different carbon substrates. Because modified S. wolfei proteins are sufficiently abundant for post-translational modification (PTM) analyses without antibody enrichment, we could identify types of acylations comprehensively, observing six types (acetyl-, butyryl-, 3-hydroxybutyryl-, crotonyl-, valeryl-, hexanyl-lysine), two of which have not been reported in any system previously. All of the acyl-PTMs identified correspond directly to RACS in fatty acid degradation pathways. A total of 369 sites of modification were identified on 237 proteins. Changing the carbon substrate altered the acylation profile. Moreover, structural studies and in vitro acylation assays of a heavily modified enzyme, acetyl-CoA transferase, provided insight on the possible impact of these acyl-protein modifications. Our findings link protein acylation by RACS to shifts in cellular metabolism.

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“…Initially, Zhao et al developed an antibody against acetylated proteins [10], that opened the path to large acetylome and other acylomes studies [11][12][13], when combining the PTM enrichments with liquid chromatography-tandem mass spectrometry (LC-MS/MS). These reversible acyl modifications result from donation of a malonyl or succinyl group onto the ε-amino group of lysine sidechains either enzymatically by dedicated acyltransferases [14][15][16] or in non-enzymatic reactions [17][18][19][20]. These added negativelycharged carboxyl moieties change the net charge of lysine residues from a positive (+1) to a negative (-1) charge at physiological pH, which alter the physical and chemical properties of the proteins and impact their structures and interactions.…”

Section: Introductionmentioning

confidence: 99%

“…These added negativelycharged carboxyl moieties change the net charge of lysine residues from a positive (+1) to a negative (-1) charge at physiological pH, which alter the physical and chemical properties of the proteins and impact their structures and interactions. Dysregulation of protein acylation is involved in cancer metastasis, diabetes and neurodegenerative diseases [16,21]. Specific lysine deacylases catalyze the removal of the acylation groups, and include members of the sirtuin family [16,22].…”

Section: Introductionmentioning

confidence: 99%

“…Dysregulation of protein acylation is involved in cancer metastasis, diabetes and neurodegenerative diseases [16,21]. Specific lysine deacylases catalyze the removal of the acylation groups, and include members of the sirtuin family [16,22]. Sirtuins are a class of nicotinamide adenine dinucleotide (NAD + )-dependent deacylases, with seven members in mammals (SIRT1 -7) that differ in subcellular localization, activity and substrate specificity [21].…”

Section: Introductionmentioning

confidence: 99%

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In-depth Analysis of the Sirtuin 5-regulated Mouse Brain Acylome using Library-free Data-Independent Acquisitions

Bons

Rose

Zhang

et al. 2022

Preprint

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Post-translational modifications (PTMs) dynamically regulate proteins and biological pathways, typically through the combined effects of multiple PTMs. Lysine residues are targeted for various PTMs, including malonylation and succinylation. However, PTMs offer specific challenges to mass spectrometry-based proteomics during data acquisition and processing. Thus, novel and innovative workflows using data-independent acquisition (DIA) ensure confident PTM identification, precise site localization, and accurate and robust label-free quantification. In this study, we present a powerful approach that combines antibody-based enrichment with comprehensive DIA acquisitions and spectral library-free data processing using directDIA (Spectronaut). Identical DIA data can be used to generate spectral libraries and comprehensively identify and quantify PTMs, reducing the amount of enriched sample and acquisition time needed, while offering a fully automated workflow. We analyzed brains from wild-type and Sirtuin 5 (SIRT5)-knock-out mice, and discovered and quantified 466 malonylated and 2,211 succinylated peptides. SIRT5 regulation remodeled the acylomes by targeting 171 malonylated and 640 succinylated sites. Affected pathways included carbohydrate and lipid metabolisms, synaptic vesicle cycle, and neurodegenerative diseases. We found 48 common SIRT5-regulated malonylation and succinylation sites, suggesting potential PTM crosstalk. This innovative and efficient workflow offers deeper insights into the mouse brain lysine malonylome and succinylome.

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An Expanding Repertoire of Protein Acylations

Cited by 44 publications

References 168 publications

The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy

The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy

Dynamic acylome reveals metabolite driven modifications in Syntrophomonas wolfei

In-depth Analysis of the Sirtuin 5-regulated Mouse Brain Acylome using Library-free Data-Independent Acquisitions

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