Dataset Information

Phosphoproteomics analysis of TAMs with NEK2 overexpression

ABSTRACT: NEK2 is considered a key factor in the maintenance of development and function of B cells in multiple myeloma (MM). Importantly, we previously demonstrated that PD-L1 is a substrate of NEK2, and combinatorial inhibition of NEK2 and PD-L1 largely improves the therapeutic efficacy of pancreatic cancer in pre-clinical models. But the expression and function of NEK2 in HCC-related TAMs have not yet been studied. This analysis revealed changes in the proteome due to the overexpression of NEK2 in TAMs, providing a valuable reference for further functional investigations.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Xiaozhen Zhang

LAB HEAD: Xiaozhen Zhang

PROVIDER: PXD054708 | Pride | 2025-05-26

REPOSITORIES: Pride

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Sphingolipid synthesis in tumor-associated macrophages confers immunotherapy resistance in hepatocellular carcinoma.

Zhang Xiaozhen X Lao Mengyi M Sun Kang K Yang Hanshen H He Lihong L Liu Xinyuan X Liu Linyue L Zhang Sirui S Guo Chengxiang C Wang Sicheng S Shi Jiatao J Zhang Xiaoyu X Xu Daqian D Lu Xiongbin X Bai Xueli X Liang Tingbo T

Science advances 20250521 21

Dysregulated metabolism of immune cells in the tumor microenvironment leads to immune evasion and tumor progression. As a major cell component in the tumor, the metabolic reprogramming of tumor-associated macrophages (TAMs) creates an immunosuppressive microenvironment in hepatocellular carcinoma (HCC). Our study found that sphingolipid (particularly, sphingosine-1-phosphate or S1P) levels are a clinical indicator for prognosis and immunotherapy response in patients with HCC. S1P primarily deriv ...[more]

PMID: 40397754

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Project description:Clinical therapeutic human serum albumin (HSA) preparations are manufactured by human plasma from donors and contain some miscellaneous proteins (MPs) except albumin. Multiple studies have demonstrated significant variations in the extent of post-translation modifications, redox states, and antioxidant capacities among HSA preparations from different manufacturers. However, these studies have primarily focused on the albumin molecule itself and have not conducted detailed analysis and comparison of the MPs present in HSA preparations. While there have been a few studies that have reported on the presence of MPs in commercial HSA preparations, research in this area is still relatively scarce. In this study, we employed 4D Label-Free quantitative proteomic technology to conduct identification and analysis of MPs in preparations of human plasma-derived HSA (pHSA) from 6 distinct manufacturers; Additionally, we investigated MPs in recombinant HSA (rHSA) preparations obtained through expression in yeast and rice. There were total 456 different MPs identified in 6 pHSA samples and 96 MPs were detected in all pHSA samples. 52 MPs in the rHSA (expressed in yeast) sample and 152 in the rHSA (expressed in rice) were identified. Haptoglobin, Hemopexin and Transthyretin included the top 8 MPs with the highest relative abundance detected in every pHSA preparations in this study. Bioinformatics (including GO, COG/KOG, KEGG, protein−protein interactions, etc.) analysis showed that the MPs identified in pHSA were basically involved in endopeptidase inhibitor activity, complement and coagulation cascades, biosynthesis of amino acids and cholesterol metabolism. Validation results demonstrated that HP, HPX, TF and TTR could be detected in pHSA but not in rHSA, which were consistent with 4D Label-Free quantitative proteomic results. Compared with previous studies, more trace MPs were detected in pHSA and rHSA preparations by 4D Label-Free quantitative proteomic technology. This could provide a new approach for high-throughput detection of trace MPs in HSA preparations.

Project description:Phosphorylation is well-known in regulating various biological processes. However, comprehensively phosphoproteomic profiling in the termination of liver regeneration (LR) is still missing. Here, we used TMT labeling coupled with phosphopeptides enrichment and 2D LC-MS/MS analysis to establish a global phosphoproteomic map in mice liver at day 5 after partial hepatectomy. Altogether, 619 phosphorylation sites in 437 proteins were significantly up-regulated and 503 phosphorylation sites in 358 proteins were down-regulated. The differentially phosphorylated proteins were further classified according to their biological process, cellular components, molecular function and subcellular localization. KEGG pathway analysis showed that they mainly participate in metabolic pathways, DNA replication, tight junction and focal adhesion. Motif analysis of the identified phosphorylation sites has revealed a diverse array of consensus sequences, suggesting multiple kinase families such as MAPK, PKA/PKC, CaMK-II, CKII and CDK, may be involved in the termination of LR. Finally, several differentially phosphorylated proteins were validated by Co-immunoprecipitation and Western blot. Taken together, our data unravels the first comprehensive phosphoproteomic map in the termination of liver regeneration in mice, which greatly expands our knowledge in the complicate regulation of this process and provides new directions on the treatment of liver cancer using liver resection and donor liver transplantation. Biological significance: The novelty of this study is that we have established for the first time a global phosphoproteomic map in mice liver at day 5 after partial hepatectomy, which represents the termination of liver regeneration. Altogether, 9,775 phosphorylation sites in 3,458 proteins were identified, among which 7,738 phosphorylation site in 2,971 proteins were quantified. KEGG pathway analysis demonstrates markedly metabolic reprograming in termination of LR, which is further validated by selected validation of several differentially phosphorylated metabolic enzymes such as PDHA, ACACA and FASN. The consistent high phosphorylation of PDHA in the first 4 days and its rapidly decreased phosphorylation at day 5 after PH might be a key signal in controlling the switch between glycolysis and oxidative

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