Malonylome analysis uncovers the association of lysine malonylation with metabolism and acidic stress in pathogenic Mycobacterium tuberculosis

Bi, Jianzhong; Guo, Qinglong; Zhou, Ziyuan; Huang, Xiujing; Qin, Linxiu; Tao, Xiaoyu; Ye, Taosheng; Chen, Liang; Li, Guobao; Wang, Zhaoqin; Liu, Lei; Zhang, Guoliang

doi:10.1016/j.micres.2022.127209

Cited by 2 publications

(3 citation statements)

References 65 publications

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“…Like other large-scale studies of malonylation in bacteria ( Qian et al., 2016 ; Shi et al., 2021 ; Bi et al., 2022 ), our data revealed that many Kmal substrates were enriched in ribosomal and translation-associated proteins, but there is no report revealing the functional role of Kmal in translation. Few studies have investigated the impacts of PTMs on ribosomal proteins.…”

Section: Discussionsupporting

confidence: 67%

“…The most heavily malonylated proteins included putative bacitracin synthetase 1 (14 sites), pyruvate kinase (12 sites), and chaperone protein DnaK (10 sites). Moreover, the proportion of malonylated proteins among the total proteins of S. mutans UA159 was about 8.1% (159/1953); these proportions for in E. coli ( Qian et al., 2016 ) was 13.8% (594/4306), 10.2% (382/3728) in B. amyloliquefaciens ( Fan et al., 2017 ), 25.7% (1026/3993) in M. tuberculosis ( Bi et al., 2022 ), and 9.7% (281/2889) in S. aureus ( Shi et al., 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…Most studies on Kmal have been performed in mammalian systems and identified thousands of malonylated sites, revealing its role in the progress of diseases like type 2 diabetes, schizophrenia, and cardiac hypertrophy ( Du et al., 2015 ; Smith et al., 2022 ; Wu et al., 2022 ). There has been increasing interest in dissecting the regulatory roles of Kmal in several bacterial species, such as Escherichia coli ( Qian et al., 2016 ), Bacillus amyloliquefaciens ( Fan et al., 2017 ), Mycobacterium tuberculosis ( Bi et al., 2022 ), and Staphylococcus aureus ( Shi et al., 2021 ), which demonstrates that Kmal exists in diverse prokaryotic organisms and participates in the regulation of various physiological processes. Even so, whether Kmal exists and affects protein functions in streptococci remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Systematic analysis of lysine malonylation in Streptococcus mutans

Zhang

et al. 2022

Front. Cell. Infect. Microbiol.

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Protein lysine malonylation (Kmal) is a novel post-translational modification (PTM) that regulates various biological pathways such as energy metabolism and translation. Malonylation in prokaryotes, however, is still poorly understood. In this study, we performed a global Kmal analysis of the cariogenic organism Streptococcus mutans by combining antibody-based affinity enrichment and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis. Altogether, 392 malonyllysine sites in 159 proteins were identified. Subsequent bioinformatic analysis revealed that Kmal occurs in proteins involved in various metabolic pathways including translation machinery, energy metabolism, RNA degradation, and biosynthesis of various secondary metabolites. Quantitative analysis demonstrated that Kmal substrates were globally altered in the biofilm growth state compared to the planktonic growth state. Furthermore, a comparative analysis of the lysine malonylome of our study with previously determined lysine acetylome in S. mutans revealed that a small proportion of Kmal sites overlapped with acetylated sites, whereby suggesting that these two acylations have distinct functional implications. These results expand our knowledge of Kmal in prokaryotes, providing a resource for researching metabolic regulation of bacterial virulence and physiological functions by PTM.

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Section: Discussionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systematic analysis of lysine malonylation in Streptococcus mutans

Zhang

et al. 2022

Front. Cell. Infect. Microbiol.

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Characterization of acidic lysine acylations in mycobacteria

Ye,

Wang,

Sun

et al. 2024

Front. Microbiol.

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IntroductionProtein acetylation is an extensively investigated post-translational modification (PTM). In addition to lysine acetylation, three new types of lysine acylations characterized by the presence of an acidic carboxylic group have been recently identified and validated. These included lysine malonylation (Kmal), lysine succinylation (Ksucc) and lysine glutarylation (Kglu). Pathogens belonging to the genus Mycobacterium elicit severe diseases in mammalian hosts through the modulation of energy metabolism pathways. Throughout this process, malonyl-CoA, succinyl-CoA and glutaryl-CoA are important intermediates in metabolic pathways, including the tricarboxylic acid (TCA) cycle, amino acid and lipid metabolism. These short-chain acyl-CoAs serve as substrates for corresponding acidic lysine acylation reactions. However, the landscape of these acyl-CoAs dependent acidic lysine acylomes remains unclear.MethodsWe used the high-affinity antibody enrichment combined with high-resolution LC-MS/MS analysis to systematically investigate the global proteomic characteristics of the three acidic lysine acylations in Mycobacterium smegmatis. Subsequently, we employed in vitro enzymatic assays to validate the functional impact of acylated substrates, adenylate kinase and proteasome-associated ATPase. Furthermore, we investigated the effects of overexpressing these two substrates on the in vitro growth of Mycobacterium smegmatis, its invasion of THP-1 cells, and the influence on inflammatory cytokines.ResultsWe systematically investigated the global substrate characterization of 1,703 lysine malonylated sites, 5,320 lysine succinylated sites and 269 lysine glutarylated sites in the non-pathogenic model strain Mycobacterium smegmatis. Bioinformatics analysis demonstrated a correlation between these acidic lysine acylations and the functional roles of ribosomes, in addition to their roles in various metabolic pathways. Furthermore, we investigated the impact of lysine acylations on the functional activity of adenylate kinase and proteasome-associated ATPase, as well as their roles in mycobacterial infection process.DiscussionCollectively, our study provided an important resource on substrate characterization and functional regulation of acidic lysine acylations in Mycobacterium smegmatis, giving valuable insights into their interrelation with the biology of infectious process.

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Malonylome analysis uncovers the association of lysine malonylation with metabolism and acidic stress in pathogenic Mycobacterium tuberculosis

Cited by 2 publications

References 65 publications

Systematic analysis of lysine malonylation in Streptococcus mutans

Systematic analysis of lysine malonylation in Streptococcus mutans

Characterization of acidic lysine acylations in mycobacteria

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