bims-meprid 2023-06-25 papers

Issue of 2023‒06‒25
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

J Neuroinflammation. 2023 Jun 22. 20(1): 146

Ogt-mediated O-GlcNAcylation inhibits astrocytes activation through modulating NF-κB signaling pathway.

Xiaoxue Dong, Liqi Shu, Jinyu Zhang, Xu Yang, Xuejun Cheng, Xingsen Zhao, Wenzheng Qu, Qiang Zhu, Yikai Shou, Guoping Peng, Binggui Sun, Wen Yi, Qiang Shu, Xuekun Li.

Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3β binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aβ plaque of AD mice in vitro and in vivo. Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway.

DOI: https://doi.org/10.1186/s12974-023-02824-8

Cell Rep. 2023 Jun 21. pii: S2211-1247(23)00677-0. [Epub ahead of print]42(7): 112666

Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression.

Yan Zheng, Le Zhu, Zhao-Yu Qin, Yu Guo, Shun Wang, Min Xue, Ke-Yu Shen, Bei-Yuan Hu, Xu-Feng Wang, Chao-Qun Wang, Lun-Xiu Qin, Qiong-Zhu Dong.

Protein lysine crotonylation has been recently identified as a vital posttranslational modification in cellular processes, particularly through the modification of histones. We show that lysine crotonylation is an important modification of the cytoplastic and mitochondria proteins. Enzymes in glycolysis, the tricarboxylic acid (TCA) cycle, fatty acid metabolism, glutamine metabolism, glutathione metabolism, the urea cycle, one-carbon metabolism, and mitochondrial fusion/fission dynamics are found to be extensively crotonylated in pancreatic cancer cells. This modulation is mainly controlled by a pair of crotonylation writers and erasers including CBP/p300, HDAC1, and HDAC3. The dynamic crotonylation of metabolic enzymes is involved in metabolism regulation, which is linked with tumor progression. Interestingly, the activation of MTHFD1 by decrotonylation at Lys354 and Lys553 promotes the development of pancreatic cancer by increasing resistance to ferroptosis. Our study suggests that crotonylation represents a metabolic regulatory mechanism in pancreatic cancer progression.

Keywords: CP: Cancer; CP: Molecular biology; MTHFD1; crotonylation; metabolism; pancreatic cancer; tumor progression

DOI: https://doi.org/10.1016/j.celrep.2023.112666

Nat Metab. 2023 Jun 19.

Enhanced BCAT1 activity and BCAA metabolism promotes RhoC activity in cancer progression.

Lin Qian, Na Li, Xiao-Chen Lu, Midie Xu, Ying Liu, Kaiyue Li, Yi Zhang, Kewen Hu, Yu-Ting Qi, Jun Yao, Ying-Li Wu, Wenyu Wen, Shenglin Huang, Zheng-Jun Chen, Miao Yin, Qun-Ying Lei.

Increased expression of branched-chain amino acid transaminase 1 or 2 (BCAT1 and BCAT2) has been associated with aggressive phenotypes of different cancers. Here we identify a gain of function of BCAT1 glutamic acid to alanine mutation at codon 61 (BCAT1E61A) enriched around 2.8% in clinical gastric cancer samples. We found that BCAT1E61A confers higher enzymatic activity to boost branched-chain amino acid (BCAA) catabolism, accelerate cell growth and motility and contribute to tumor development. BCAT1 directly interacts with RhoC, leading to elevation of RhoC activity. Notably, the BCAA-derived metabolite, branched-chain α-keto acid directly binds to the small GTPase protein RhoC and promotes its activity. BCAT1 knockout-suppressed cell motility could be rescued by expressing BCAT1E61A or adding branched-chain α-keto acid. We also identified that candesartan acts as an inhibitor of BCAT1E61A, thus repressing RhoC activity and cancer cell motility in vitro and preventing peritoneal metastasis in vivo. Our study reveals a link between BCAA metabolism and cell motility and proliferation through regulating RhoC activation, with potential therapeutic implications for cancers.

DOI: https://doi.org/10.1038/s42255-023-00818-7

Trends Parasitol. 2023 Jun 20. pii: S1471-4922(23)00128-9. [Epub ahead of print]

Navigating the boundaries between metabolism and epigenetics in trypanosomes.

Ana Paula Menezes, Ana Milena Murillo, Camila Gachet de Castro, Natalia Karla Bellini, Luiz Ricardo Orsini Tosi, Otavio Henrique Thiemann, Maria Carolina Elias, Ariel Mariano Silber, Julia Pinheiro Chagas da Cunha.

Epigenetic marks enable cells to acquire new biological features that favor their adaptation to environmental changes. These marks are chemical modifications on chromatin-associated proteins and nucleic acids that lead to changes in the chromatin landscape and may eventually affect gene expression. The chemical tags of these epigenetic marks are comprised of intermediate cellular metabolites. The number of discovered associations between metabolism and epigenetics has increased, revealing how environment influences gene regulation and phenotype diversity. This connection is relevant to all organisms but underappreciated in digenetic parasites, which must adapt to different environments as they progress through their life cycles. This review speculates and proposes associations between epigenetics and metabolism in trypanosomes, which are protozoan parasites that cause human and livestock diseases.

Keywords: S-adenosyl methionine; acetyl-CoA; epigenetics; histone; metabolism; trypanosomes

DOI: https://doi.org/10.1016/j.pt.2023.05.010

J Biol Chem. 2023 Jun 16. pii: S0021-9258(23)01966-X. [Epub ahead of print] 104938

Intrinsic catalytic properties of histone H3 lysine-9 methyltransferases preserve monomethylation levels under low S-adenosylmethionine.

Spencer A Haws, Lillian J Miller, Diego Rojas La Luz, Vyacheslav I Kuznetsov, Raymond C Trievel, Gheorghe Craciun, John M Denu.

S-adenosylmethionine (SAM) is the methyl donor for site-specific methylation reactions on histone proteins, imparting key epigenetic information. During SAM-depleted conditions that can arise from dietary methionine restriction, lysine di- and tri-methylation are reduced while sites such as Histone-3 lysine-9 (H3K9) are actively maintained, allowing cells to restore higher-state methylation upon metabolic recovery. Here, we investigated if the intrinsic catalytic properties of H3K9 histone methyltransferases (HMTs) contribute to this epigenetic persistence. We employed systematic kinetic analyses and substrate binding assays using four recombinant H3K9 HMTs (i.e., EHMT1, EHMT2, SUV39H1, and SUV39H2). At both high and low (sub-saturating) [SAM], all HMTs displayed the highest catalytic efficiency (kcat/KM) for monomethylation compared to di- and trimethylation on H3 peptide substrates. The favored monomethylation reaction was also reflected in kcat values, apart from SUV39H2 which displayed a similar kcat regardless of substrate methylation state. Using differentially-methylated nucleosomes as substrates, kinetic analyses of EHMT1 and EHMT2 revealed similar catalytic preferences. Orthogonal binding assays revealed only small differences in substrate affinity across methylation states, suggesting that catalytic steps dictate the monomethylation preferences of EHMT1, EHMT2, and SUV39H1. To link in vitro catalytic rates with nuclear methylation dynamics, we built a mathematical model incorporating measured kinetic parameters and a time course of mass spectrometry-based H3K9 methylation measurements following cellular SAM depletion. The model revealed that the intrinsic kinetic constants of the catalytic domains could recapitulate in vivo observations. Together, these results suggest catalytic discrimination by H3K9 HMTs maintain nuclear H3K9me1, ensuring epigenetic persistence after metabolic stress.

Keywords: S-adenosylmethionine; histone; kinetics; metabolism; methyltransferase; nucleosome

DOI: https://doi.org/10.1016/j.jbc.2023.104938