bims-meprid 2025-04-20 papers

Trends Cell Biol. 2025 Apr 16. pii: S0962-8924(25)00090-X. [Epub ahead of print]

New job for an old tool: PI3Kβ phosphorylates OGT to regulate acetyl-CoA in glioblastoma.

Riley G Young, Nusaiba N Ahmed, Mauricio J Reginato.

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PI3Kβ) is recognized for its role in cellular signaling as a lipid kinase. He and colleagues recently reported a non-canonical function of PI3Kβ where, under high glucose, it phosphorylates and activates O-GlcNAc transferase (OGT). This activation enhances ATP-citrate synthase (ACLY) O-GlcNAcylation, increasing acetyl-CoA production, fueling fatty acid metabolism and histone acetylation, and driving glioblastoma (GBM) growth.

Keywords: ACLY; HK1; O-GlcNAc transferase; PI3Kβ; acetyl-CoA; acetylation; glioblastoma; kinase

DOI: https://doi.org/10.1016/j.tcb.2025.04.002

Toxicol Appl Pharmacol. 2025 Apr 16. pii: S0041-008X(25)00123-1. [Epub ahead of print] 117347

H3K9/18 lactylation regulates DNA damage due to nickel exposure in human bronchial epithelial cells.

Xiaomin Xie, Chaowei Wen, Quekun Peng, Daimin Xiang, Xinyi Pan, Xinmei Lan, Zijian Chen, Xiaohui Hua, Guiying Wang, Chuanshu Huang.

Nickel, a well-known heavy metal with lung carcinogenic properties, is recognized for its effects on cellular metabolism, oxidative stress, and gene expression. While these cellular alterations have prompted investigations into its potential impact on histone modifications, specific associations with histone lactylation remain under exploration. In the present study, we demonstrate that nickel exposure induces lactylation of histone H3 at lysines 9 (H3K9) and 18 (H3K18), accompanied by reactive oxygen species (ROS) accumulation and DNA damage in human bronchial epithelial Beas-2B cells. Inhibition of H3K9 and H3K18 lactylation, achieved by overexpressing mutated H3K9R and H3K18R, respectively, markedly abolishes ROS generation and DNA damage caused by nickel exposure. This highlights the novel biological effects of H3K9 and H3K18 lactylation in nickel-induced lung toxicity. Mechanistic investigations show that nickel-induced lactylation of H3K9 and H3K18 is mediated by elevated LDHA expression, leading to lactate accumulation, which results from the upregulation of LDHA mRNA transcription through HIF-1α/c-Jun axis and enhanced LDHA protein stability via TNF-α-mediated induction of HSP70, respectively. Our findings uncover a novel effect of nickel exposure on histone H3 lactylation and its biological impact on ROS accumulation and DNA damage through the HIF-1α/c-Jun/LDHA and TNF-α/HSP70/LDHA pathways. These results provide significant insights into the role of histone lactylation in heavy metal-induced lung toxicity.

Keywords: DNA Damage; Histone H3 Lysine Lactylation; LDHA; Nickel; ROS

DOI: https://doi.org/10.1016/j.taap.2025.117347

Nat Microbiol. 2025 Apr 18.

Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.

Wenjun Xia, Youxiang Mao, Ziyan Xia, Jie Cheng, Peng Jiang.

Metabolic remodelling underpins macrophage effector functions in response to various stimuli, but the mechanisms involved are unclear. Here we report that viral-infection-induced inflammatory stimulation causes a rewiring of the urea cycle and the tricarboxylic acid cycle metabolism in macrophages to form a cyclic pathway called the aspartate-argininosuccinate (AAS) shunt. Using RNA sequencing, unbiased metabolomics and stable isotope tracing, we found that fumarate generated from the AAS shunt is driven by argininosuccinate synthase (ASS1) in the cytosol and potentiates inflammatory effects. Genetic ablation of ASS1 reduces intracellular fumarate levels and interferon-β production, and mitochondrial respiration is also suppressed. Notably, viral challenge or fumarate esters enhance interferon-β production via direct succination of the mitochondrial antiviral signalling protein and activation of the retinoic acid-inducible gene-I-like receptor signalling. In addition to the vesicular stomatitis virus, the Sendai virus and influenza A virus can also exert these effects. In addition, patients with Ebola virus disease have increased ASS1 expression and ASS1-deficient mice show suppressed macrophage interferon responses to vesicular stomatitis virus infection. These findings reveal that fumarate can be produced from the viral inflammation-induced AAS shunt and is essential for antiviral innate immunity.

DOI: https://doi.org/10.1038/s41564-025-01985-x