Dataset Information

Cholangiocarcinoma PDHA1 Succinylation Suppresses Macrophage Antigen Presentation via α-KG Accumulation

ABSTRACT: Cholangiocarcinoma, ranking as the second most prevalent primary hepatic malignancy following hepatocellular carcinoma, is distinguished by its aggressive invasiveness and grim prognosis. Over the past decade, chemotherapy has persisted as the standard first-line treatment for cholangiocarcinoma; However, the outcomes in terms of efficacy and patient survival have remained disappointingly suboptimal due to the emergence of chemotherapy resistance issues. Thus, a newer and deeper understanding of pathways to regulate cholangiocarcinoma progression and sentisize chemotherapy therapy is needed. Metabolic reprogramming is a hallmark of cancer, intricately linked to post-translational modifications . The critical role of novel acyl modifications in tumorigenesis has garnered widespread attention in recent years . Succinylation, a new post-translational modification occurring on lysine residues, is involved in many core energy metabolic pathways, including the tricarboxylic acid cycle and glucose metabolism, and plays a role in regulating the progression of various tumors. In this study, from the perspective of succinylation modification, we explore a novel mechanism of cholangiocarcinoma progression and proposed a new direction for sensitized chemotherapy treatment.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: Ning Zhang

LAB HEAD: Ning Zhang

PROVIDER: PXD060091 | Pride | 2025-05-07

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	N1_Slot2-23_1_6778.d.zip	Other
	N2_Slot2-25_1_6782.d.zip	Other
	N3_Slot2-27_1_6786.d.zip	Other
	N4_Slot2-29_1_6790.d.zip	Other
	N5_Slot2-31_1_6794.d.zip	Other

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Publications

Cholangiocarcinoma PDHA1 succinylation suppresses macrophage antigen presentation via alpha-ketoglutaric acid accumulation.

Zhang Ning N Sun Linmao L Zhou Shuo S Ji Changyong C Cui Tianming T Chu Qi Q Ye Jiareng J Liang Shuhang S Ma Kun K Liu Yufeng Y Li Xianying X Guo Xinyu X Zhang Weizhi W Gu Xuetian X Cheng Cheng C Zha Qingrui Q Tao Shengwei S Zhang Yunguang Y Chu Junhui J Wu Chenghui C Zhang Yuchen Y Wang Jiabei J Liu Yao Y Liu Lianxin L

Nature communications 20250403 1

Gemcitabine combined with cisplatin is the first-line chemotherapy for advanced cholangiocarcinoma, but drug resistance remains a challenge, leading to unsatisfactory therapeutic effect. Here, we elucidate the possibility of chemotherapy regimens sensitized by inhibiting succinylation in patients with cholangiocarcinoma from the perspective of post-translational modification. Our omics analysis reveals that succinylation of PDHA1 lysine 83, a key enzyme in the tricarboxylic acid cycle, alters PD ...[more]

PMID: 40180922

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Project description:This study aims to analyze and compare the post-translational modification differences between human plasma- and genetic recombination-derived human serum albumin (HSA) in clinical treatments in China. 6 different post-translational modifications, including acetylation, succinylation, crotonylation, phosphorylation, beta-hydroxybutyrylation, and lactylation, were detected using pan-specific antibodies through Western blot. The samples, consisting of human plasma-derived HSA (pHSA) from six different manufacturers and recombinant HSA (rHSA) expressed in yeast and oryza sativa, underwent detection of types of post-translational modifications. 4D label-free PTMs quantitative proteomic analysis was conducted to detect N-glycosylation and the above-mentioned post-translational modifications in pHSA and rHSA samples, and analyze the differences in modification sites and levels. Through Western blot analysis, all six pHSA and two rHSA samples were positive in the band of albumin (66.5 kDa) for the six post-translational modifications. Further analysis using 4D label-free PTMs quantitative proteomics revealed 25 (29) acetylated, 30 (32) succinylated, 41 (50) malonylated, 15 (23) phosphorylated, 36 (30) beta-hydroxybutyrylated, and 27 (34) lactylated modification sites in pHSA and rHSA samples and no N-glycosylation modification sites. The analysis results identified 1 acetylation (ALB_K160), 2 beta-hydroxybutyrylation (ALB_K569, ALB_K426), 3 crotonylation (ALB_K264, ALB_K581, ALB_K560), and 15 phosphorylation specific modification sites in pHSA, as well as 3 crotonylation (ALB_K560, ALB_K562, ALB_K75), 1 succinylation (ALB_K490), and 23 phosphorylation specific modification sites in rHSA. In pHSA (rHSA), 2 (6) acetylation, 10 (12) succinylation, 0 (9) crotonylation, 1 (9) phosphorylation, 6 (0) beta-hydroxybutyrylation, and 0 (7) lactylation specific modification sites were found. Additionally, in the common modification sites of pHSA and rHSA, pHSA showed up-regulation of amberylation (16:1) and beta-hydroxybutyrylation (12:2) in more sites, and up-regulation of acetylation (7:11), crotonylation (2:11), phosphorylation (1:8), and lactylation (1:14) in less sites compared to rHSA. In clinical treatment, the used pHSA and rHSA in China generally exhibit acetylation, succinylation, crotonylation, phosphorylation, beta-hydroxybutyrylation, and lactylation, and there are differences in the site characteristics and modification levels of these modifications between pHSA and rHSA. Further experimental investigations are needed to explore the impact of post-translational modification differences on the biological function, efficacy, and safety of pHSA and rHSA.

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.