Dataset Information

Deep Succinylproteomics of Brain Tissues of Intracerebral Hemorrhage with inhibition of Toll-like receptor 4 signaling

ABSTRACT: The details of Toll-like receptor (TLR) 4 signaling affects protein succinylation in intracerebral hemorrhage (ICH) brains remains completely unclear. In this study, we constructed mice ICH models to investigate the changes in ICH-associated brain protein succinylation with the treatment of TLR4 antagonist, TAK242, using a high-resolution mass spectrometry-based, quantitative succinyllysine proteomics approach. We characterized a concentration of approximately 6700 succinylation events and quantified approximately 3500 sites, highlighting 139 succinyllysine site changes in 40 pathways. Further analysis showed that TAK242 treatment induced an increase in 29 succinyllysine sites of 28 succinylated proteins and reduction of 24 succinyllysine sites on 23 succinylated proteins in ICH brains. Both the TAK242 treatment induced hypersuccinylated and hyposuccinylated proteins in ICH brains were mainly located in mitochondria and cytoplasm. GO analysis showed that TAK242 treatment induced changes in ICH-associated succinylated proteins were mostly located in synapse, membrane, vesicle, etc., and enriched in many processes, such as metabolism, synapse, myeline, etc.. KEGG analysis showed that TAK242 induced downregulation of succinylation was significantly linked to fatty acid metabolism and lysosome. Moreover, a combination analysis of our succinylproteomic data with previously published transcriptome data identified that most of the differentially succinylated proteins induced by TAK242 treatment were mainly distributed into neurons, astrocytes and endothelial cells; and 7 and 3 of these succinylated proteins significantly high express in neurons and astrocytes, respectively. In conclusion, our analyses uncover a number of TLR4 signaling affected succinylation processes and pathways in mouse ICH brains and provide new insights for understanding ICH pathophysiological processes.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Xiao-Yi Xiong

LAB HEAD: Xiaoyi Xiong

PROVIDER: PXD025622 | Pride | 2021-11-03

REPOSITORIES: Pride

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Deep Succinylproteomics of Brain Tissues from Intracerebral Hemorrhage with Inhibition of Toll-Like Receptor 4 Signaling.

Liang Yan-Jing YJ Yang Yuan-Rui YR Tao Chuan-Yuan CY Yang Su-Hao SH Zhang Xin-Xiao XX Yuan Jing J Deng Yuan-Hong YH Zhong Zhan-Qiong ZQ Yu Shu-Guang SG Xiong Xiao-Yi XY

Cellular and molecular neurobiology 20210830 8

It is unclear how Toll-like receptor (TLR) 4 signaling affects protein succinylation in the brain after intracerebral hemorrhage (ICH). Here, we constructed a mouse ICH model to investigate the changes in ICH-associated brain protein succinylation, following a treatment with a TLR4 antagonist, TAK242, using a high-resolution mass spectrometry-based, quantitative succinyllysine proteomics approach. We characterized the prevalence of approximately 6700 succinylation events and quantified approxima ...[more]

PMID: 34460038

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Project description:Background Hypothyroidism is a common disease, and its molecular mechanism still needs further investigation. Succinylation, as a newly identified protein posttranslational modification, is found to be involved in various metabolisms and cellular processes. In the present study, we performed quantitative analysis of the lysine succinylome in the thyroid of rats with hypothyroxinemia. Methods Hypothyroxinemia was induced in rats through the administration of a high-fat diet and then the thyroid tissues were taken out for further analysis. Affinity enrichment and liquid chromatography-tandem mass spectrometry techniques were applied for the quantitative proteome and succinylome analyses, respectively. Bioinformatic analyses were performed to decipher the differentially expressed proteins and succinylated sites, including the gene ontology (GO) annotation-based classification, Wolfpsort-based subcellular localization prediction, Kyoto Encyclopedia of Genes and Genomes (KEGG)-based functional pathway enrichment, and conserved domains of protein and succinylation sites prediction. Finally, the mitochondrial oxygen consumption rates of human normal thyroid epithelial cells were measured to further verify the role of lysine succinylation in vitro. Results Overall, 3869 proteins were identified, among which 129 differentially expressed proteins were quantified. Downregulated expressed proteins were enriched in the thyroid hormone synthesis and thyroid hormone signaling pathways and were mainly localized to the mitochondria and ATPase complex. In addition, 685 lysine succinylation sites on 250 proteins were identified, of which 172 lysine succinylation sites on 104 proteins were obvious changed (7 upregulated on 5 proteins and 165 downregulated on 99 proteins). Decreased succinylated proteins were involved in diverse metabolic pathways and biological processes, including the tricarboxylic acid cycle (TCA cycle), cellular respiration, energy derivation by oxidation of organic compounds and aerobic respiration. Moreover, these decreased succinylated proteins were primarily localized to the mitochondria. Finally, OCRs related to basal respiration, ATP production and maximal respiration were markedly blunted in the normal thyroid epithelial cells treated with palmitic acid (all p < 0.05), and the changes were reversed when the cells were treated with palmitic acid and desuccinylase inhibitor together (all p < 0.05). Conclusions The thyroid differentially expressed proteins and changed succinylation levels played a potential role in the mitochondria-mediated energy metabolism in the HFD-induced hypothyroxinemia rat model.

Project description:Background: Lysine succinylation is a newly identified PTM, which exists widely from prokaryotes to eukaryotes and participates in various cellular processes, especially in the metabolic processes. Staphylococcus epidermidis is a commensal bacterium in the skin, which attracts more attention as a pathogen, especially in immunocompromised patients and neonates by attaching to medical devices and forming biofilms. However, the significance of lysine succinylation in proteins of Staphylococcus epidermidis has not been investigated. Materials and methods: Using antibody affinity enrichment followed by LC-MS/MS analysis, we examined the succinylome of Staphylococcus epidermidis (ATCC®12228™). Then, bioinformatics analysis was performed, including Gene Ontology, KEGG enrichment, motif characterization, secondary structure, protein-protein interaction, and BLAST analysis. Results: A total of 1557 succinylated lysine sites in 649 proteins were identified in Staphylococcus epidermidis (ATCC 12228). Among these succinylation proteins, GO annotation showed that proteins related to metabolic processes and binding activity accounted for the most based on the analysis of biological process and molecular function, respectively. KEGG pathway characterization indicated that proteins associated with the glycolysis/ gluconeogenesis, and citrate cycle (TCA cycle) pathway were more likely to be succinylated. Moreover, 13 conserved motifs were identified. The specific motif KsuD was conserved in model prokaryotes and eukaryotes. Succinylated proteins with this motif were highly enriched in the glycolysis/gluconeogenesis pathway. One succinylation site(K144) was identified in S-ribosylhomocysteine lyase, a key enzyme in the quorum sensing system, indicating the regulatory role succinylation may play in bacterial processes. Furthermore, 15 succinyltransferases and 18 desuccinylases(erasers) were predicted in S.epidermidis by BLAST analysis. Conclusions: We performed the first comprehensive profile of succinylation in Staphylococcus epidermidis and illustrated the significant role succinylation may play in energy metabolism, QS system, and other bacterial behaviors. This study may be a fundamental basis to investigate the underlying mechanisms of colonization, virulence, and infection of S. epidermidis, as well as provide a new insight into regulatory effects succinylation may lay on metabolic processes.

			Action	DRS
	HA163LPSc_Sharm1.raw	Raw
	HA163LPSc_Sharm2.raw	Raw
	HA163LPSc_Sharm3.raw	Raw
	HA163LPSc_TAK242_ICH1.raw	Raw
	HA163LPSc_TAK242_ICH2.raw	Raw