A Landscape map of multiple posttranslational modifications in hepatocellular carcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Beicheng Sun
PROVIDER: PXD058966 | iProX | Wed Dec 18 00:00:00 GMT 2024
REPOSITORIES: iProX
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Project description:Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-CoA carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. It is discovered that a malonylation-mimic mutant in ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.
2023-03-05 | GSE226139 | GEO
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.
2024-05-09 | PXD050752 | Pride
Project description:Protein acylation links energetic substrate flux with cellular adaptive responses. SIRT5 is a NAD+-dependent lysine deacylase and removes both succinyl and malonyl group. Using affinity enrichment and label free quantitative proteomics, we characterized the SIRT5-regulated lysine malonylome in wild type (WT) and Sirt5-/- mice. 1137 malonyllysine sites were identified across 430 proteins, with 183 sites (from 120 proteins) significantly increased in the Sirt5-/- animals. Pathway analysis identified glycolysis as the top SIRT5-regulated pathway. Importantly, glycolytic flux was diminished in primary hepatocytes from Sirt5-/- compared to WT mice. Substitution of malonylated lysine residue 184 in glyceraldehyde 3-phosphate dehydrogenase with glutamic acid, a malonyllysine mimic, suppressed its enzymatic activity. Comparison of our previous reports on acylation reveals that malonylation targets a different set of proteins than acetylation and succinylation. These data demonstrate that SIRT5 is a global regulator of lysine malonylation and provide a mechanism for regulation of energetic flux through glycolysis.
2015-04-27 | MSV000079116 | MassIVE
Project description:Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-CoA carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. It is discovered that a malonylation-mimic mutant in ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.
2023-07-21 | PXD040481 | Pride
Project description:Histone lysine β-hydroxybutyrylation (Kbhb) links ketone metabolism to gene transcription. However, the regulatory mechanism that kenogenesis-derived β-hydroxybutyrate, present throughout cells at low concentration, orchestrates this histone mark remains largely unknown. Here, we unveil a KAT7-ACSS2 module in which ACSS2 locally generates β-hydroxybutyryl-CoA (BHB-CoA), thereby bolsters histone Kbhb through fueling KAT7. Specifically, we show that KAT7 serves as a histone β-hydroxybutyryltransferase that prefers to modulate β-hydroxybutyrylation on histone H3 lysine 9 (H3K9bhb) by utilizing ACSS2-directed BHB-CoA. Moreover, ACSS2 senses β-hydroxybutyrate and translocates into the nucleus wherein it binds to and colocalizes with KAT7 at gene promoter regions. We further show that KAT7 coupled with ACSS2 regulates specific activation of genes associated with tumor cell survival through histone Kbhb. Collectively, our findings reveal that KAT7-ACSS2 module promotes histone β-hydroxybutyrylation by providing BHB-CoA locally, highlighting the importance of linking metabolic enzyme ACSS2 and KAT7 for histone Kbhb as well as offering insight into the regulatory mechanism of cellular metabolite on epigenetic modification and gene transcription.
2025-07-02 | GSE267130 | GEO
Project description:Histone lysine β-hydroxybutyrylation (Kbhb) links ketone metabolism to gene transcription. However, the regulatory mechanism that kenogenesis-derived β-hydroxybutyrate, present throughout cells at low concentration, orchestrates this histone mark remains largely unknown. Here, we unveil a KAT7-ACSS2 module in which ACSS2 locally generates β-hydroxybutyryl-CoA (BHB-CoA), thereby bolsters histone Kbhb through fueling KAT7. Specifically, we show that KAT7 serves as a histone β-hydroxybutyryltransferase that prefers to modulate β-hydroxybutyrylation on histone H3 lysine 9 (H3K9bhb) by utilizing ACSS2-directed BHB-CoA. Moreover, ACSS2 senses β-hydroxybutyrate and translocates into the nucleus wherein it binds to and colocalizes with KAT7 at gene promoter regions. We further show that KAT7 coupled with ACSS2 regulates specific activation of genes associated with tumor cell survival through histone Kbhb. Collectively, our findings reveal that KAT7-ACSS2 module promotes histone β-hydroxybutyrylation by providing BHB-CoA locally, highlighting the importance of linking metabolic enzyme ACSS2 and KAT7 for histone Kbhb as well as offering insight into the regulatory mechanism of cellular metabolite on epigenetic modification and gene transcription.
2025-07-02 | GSE267129 | GEO
Project description:Background: Previously, we demonstrated that the ketone body, β-hydroxybutyrate, is a potent antihypertensive and reno-protective metabolite in Dahl Salt-Sensitive rats. However, the mechanism by which β-hydroxybutyrate confers these beneficial effects is understudied. Here we focused on determining whether the reno-protective effect of β-hydroxybutyrate is due to its known ability to epigenetically remodel chromatin via histone β-hydroxybutyrylation. Methods: We used the same animal protocol previously used for the discovery of the renoprotective effect of β-hydroxybutyrate. Briefly, post-weaning, male and female Dahl Salt-Sensitive rats were split into two groups and supplemented with or without 1,3-Butanediol for 6 weeks. At euthanasia, circulating β-hydroxybutyrate was quantitated. Renal homogenates were examined for histone 3 lysine 9 β-hydroxybutyrylation, chromatin occupancy, transcriptomic and proteomic profiles with validations. Results: Rats supplemented with 1,3-butanediol had higher circulating β-hydroxybutyrate, renal histone β-hydroxybutyrylation and significant remodeling of chromatin. Notably, regions of the genome associated with lipid catabolism were predominantly in an open chromatin configuration, leading to active transcription and translation. The most highly upregulated gene actively transcribed and translated was 3-hydroxy-3-methyglutaryl CoA Synthase 2 (Hmgcs2), a gene responsible for the biosynthesis of β-hydroxybutyrate in mitochondria. In contrast, regions with more compact chromatin structures contained immune function genes, protein tyrosine phosphatase receptor type C (Ptprc) and lymphocyte cytosolic protein 1 (Lcp1), which were suppressed. Conclusions: These results reveal that renal epigenetic histone β-hydroxybutyrylation is a novel mechanism by which transcriptional regulation of both energy metabolism and immune function occur concomitantly and contribute to renoprotection in the hypertensive Dahl rat.
2025-06-06 | GSE298451 | GEO
Project description:Background: Previously, we demonstrated that the ketone body, β-hydroxybutyrate, is a potent antihypertensive and reno-protective metabolite in Dahl Salt-Sensitive rats. However, the mechanism by which β-hydroxybutyrate confers these beneficial effects is understudied. Here we focused on determining whether the reno-protective effect of β-hydroxybutyrate is due to its known ability to epigenetically remodel chromatin via histone β-hydroxybutyrylation. Methods: We used the same animal protocol previously used for the discovery of the renoprotective effect of β-hydroxybutyrate. Briefly, post-weaning, male and female Dahl Salt-Sensitive rats were split into two groups and supplemented with or without 1,3-Butanediol for 6 weeks. At euthanasia, circulating β-hydroxybutyrate was quantitated. Renal homogenates were examined for histone 3 lysine 9 β-hydroxybutyrylation, chromatin occupancy, transcriptomic and proteomic profiles with validations. Results: Rats supplemented with 1,3-butanediol had higher circulating β-hydroxybutyrate, renal histone β-hydroxybutyrylation and significant remodeling of chromatin. Notably, regions of the genome associated with lipid catabolism were predominantly in an open chromatin configuration, leading to active transcription and translation. The most highly upregulated gene actively transcribed and translated was 3-hydroxy-3-methyglutaryl CoA Synthase 2 (Hmgcs2), a gene responsible for the biosynthesis of β-hydroxybutyrate in mitochondria. In contrast, regions with more compact chromatin structures contained immune function genes, protein tyrosine phosphatase receptor type C (Ptprc) and lymphocyte cytosolic protein 1 (Lcp1), which were suppressed. Conclusions: These results reveal that renal epigenetic histone β-hydroxybutyrylation is a novel mechanism by which transcriptional regulation of both energy metabolism and immune function occur concomitantly and contribute to renoprotection in the hypertensive Dahl rat.
2025-06-06 | GSE298452 | GEO
Project description:We report changes in beta-hydroxybutyrylation of lysine (K) 9 on histone H3 in the occipital cortex of mice after 48 hour fasting.
2023-08-21 | GSE168723 | GEO
Project description:The posttranslational modification lysine malonylation is found in many proteins, including histones. However, it remains unclear whether histone malonylation is regulated or functionally relevant. Here, we report that availability of malonyl-co-enzyme A (malonyl-CoA), an endogenous provider of malonyl groups, affects lysine malonylation, and that the deacylase SIRT5 selectively reduces malonylation of histones. To determine if histone malonylation is enzymatically catalyzed, we knocked down each of the 22 lysine acetyltransferases (KATs) to test their malonyltransferase potential. KAT2A knockdown reduced and KAT2A overexpression increased levels of histone malonylation, respectively. By mass spectrometry, H2B_K5 was highly malonylated and significantly regulated by SIRT5 in mouse brain and liver. Acetyl-CoA carboxylase (ACC), the malonyl-CoA producing enzyme, was partly localized in the nucleolus, and histone malonylation increased nucleolar area and ribosomal RNA expression. Levels of global lysine malonylation and ACC expression were higher in older mouse brains than younger mice. These experiments highlight the role of histone malonylation in ribosomal gene expression.
2022-04-26 | MSV000089318 | MassIVE