bims-meprid 2024-04-28 papers

Issue of 2024‒04‒28
five papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Cancer Lett. 2024 Apr 24. pii: S0304-3835(24)00296-9. [Epub ahead of print] 216903

Acetyl-CoA metabolic accumulation promotes hepatocellular carcinoma metastasis via enhancing CXCL1-dependent infiltration of tumor-associated neutrophils.

Jun-Jie Pan, Sun-Zhe Xie, Xin Zheng, Jian-Feng Xu, Hao Xu, Rui-Qi Yin, Yun-Ling Luo, Li Shen, Zheng-Ru Chen, Yi-Ran Chen, Shi-Zhe Yu, Lu Lu, Wen-Wei Zhu, Ming Lu, Lun-Xiu Qin.

High levels of acetyl-CoA are considered a key metabolic feature of metastatic cancers. However, the impacts of acetyl-CoA metabolic accumulation on cancer microenvironment remodeling are poorly understood. In this study, using human hepatocellular carcinoma (HCC) tissues and orthotopic xenograft models, we found a close association between high acetyl-CoA levels in HCCs, increased infiltration of tumor-associated neutrophils (TANs) in the cancer microenvironment and HCC metastasis. Cytokine microarray and enzyme-linked immunosorbent assays (ELISA) revealed the crucial role of the chemokine (C-X-C motif) ligand 1(CXCL1). Mechanistically, acetyl-CoA accumulation induces H3 acetylation-dependent upregulation of CXCL1 gene expression. CXCL1 recruits TANs, leads to neutrophil extracellular traps (NETs) formation and promotes HCC metastasis. Collectively, our work linked the accumulation of acetyl-CoA in HCC cells and TANs infiltration, and revealed that the CXCL1-CXC receptor 2 (CXCR2)-TANs-NETs axis is a potential target for HCCs with high acetyl-CoA levels.

Keywords: Acetyl-CoA; cancer metastasis; histone acetylation; neutrophil extracellular traps; tumor-associated neutrophils

DOI: https://doi.org/10.1016/j.canlet.2024.216903

Int Immunopharmacol. 2024 Apr 24. pii: S1567-5769(24)00642-8. [Epub ahead of print]133 112124

Acetyl-CoA-dependent ac4C acetylation promotes the osteogenic differentiation of LPS-stimulated BMSCs.

Yujia Bai, Wenjie Zhang, Lili Hao, Yiqing Zhao, I-Chen Tsai, Yipin Qi, Qiong Xu.

The impaired osteogenic capability of bone marrow mesenchymal stem cells (BMSCs) caused by persistent inflammation is the main pathogenesis of inflammatory bone diseases. Recent studies show that metabolism is disturbed in osteogenically differentiated BMSCs in response to Lipopolysaccharide (LPS) treatment, while the mechanism involved remains incompletely revealed. Herein, we demonstrated that BMSCs adapted their metabolism to regulate acetyl-coenzyme A (acetyl-CoA) availability and RNA acetylation level, ultimately affecting osteogenic differentiation. The mitochondrial dysfunction and impaired osteogenic potential upon inflammatory conditions accompanied by the reduced acetyl-CoA content, which in turn suppressed N4-acetylation (ac4C) level. Supplying acetyl-CoA by sodium citrate (SC) addition rescued ac4C level and promoted the osteogenic capacity of LPS-treated cells through the ATP citrate lyase (ACLY) pathway. N-acetyltransferase 10 (NAT10) inhibitor remodelin reduced ac4C level and consequently impeded osteogenic capacity. Meanwhile, the osteo-promotive effect of acetyl-CoA-dependent ac4C might be attributed to fatty acid oxidation (FAO), as evidenced by activating FAO by L-carnitine supplementation counteracted remodelin-induced inhibition of osteogenesis. Further in vivo experiments confirmed the promotive role of acetyl-CoA in the endogenous bone regeneration in rat inflammatory mandibular defects. Our study uncovered a metabolic-epigenetic axis comprising acetyl-CoA and ac4C modification in the process of inflammatory osteogenesis of BMSCs and suggested a new target for bone tissue repair in the context of inflammatory bone diseases.

Keywords: Ac(4)C; Acetyl-CoA; Bone marrow mesenchymal stem cells; Inflammation; Osteogenic differentiation

DOI: https://doi.org/10.1016/j.intimp.2024.112124

bioRxiv. 2024 Apr 20. pii: 2024.04.19.589802. [Epub ahead of print]

The Glycolytic Metabolite Methylglyoxal Covalently Inactivates the NLRP3 Inflammasome.

Caroline Stanton, Chavin Buasakdi, Jie Sun, Ian Levitan, Prerona Bora, Sergei Kutseikin, R Luke Wiseman, Michael J Bollong.

The NLRP3 inflammasome promotes inflammation in disease, yet the full repertoire of mechanisms regulating its activity are not well delineated. Among established regulatory mechanisms, covalent modification of NLRP3 has emerged as a common route for pharmacological inactivation of this protein. Here, we show that inhibition of the glycolytic enzyme PGK1 results in the accumulation of methylglyoxal, a reactive metabolite whose increased levels decrease NLRP3 assembly and inflammatory signaling in cells. We find that methylglyoxal inactivates NLRP3 via a non-enzymatic, covalent crosslinking-based mechanism, promoting inter- and intra-protein MICA posttranslational linkages within NLRP3. This work establishes NLRP3 as capable of sensing a host of electrophilic chemicals, both exogenous small molecules and endogenous reactive metabolites, and suggests a mechanism by which glycolytic flux can moderate the activation status of a central inflammatory signaling pathway.

DOI: https://doi.org/10.1101/2024.04.19.589802

Sci Adv. 2024 Apr 26. 10(17): eadk1045

Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation.

Thiruvaimozhi Abimannan, Velayoudame Parthibane, Si-Hung Le, Nagampalli Vijaykrishna, Stephen D Fox, Baktiar Karim, Govind Kunduri, Daniel Blankenberg, Thorkell Andresson, Takeshi Bamba, Usha Acharya, Jairaj K Acharya.

T helper 17 (TH17) cells are implicated in autoimmune diseases, and several metabolic processes are shown to be important for their development and function. In this study, we report an essential role for sphingolipids synthesized through the de novo pathway in TH17 cell development. Deficiency of SPTLC1, a major subunit of serine palmitoyl transferase enzyme complex that catalyzes the first and rate-limiting step of de novo sphingolipid synthesis, impaired glycolysis in differentiating TH17 cells by increasing intracellular reactive oxygen species (ROS) through enhancement of nicotinamide adenine dinucleotide phosphate oxidase 2 activity. Increased ROS leads to impaired activation of mammalian target of rapamycin C1 and reduced expression of hypoxia-inducible factor 1-alpha and c-Myc-induced glycolytic genes. SPTLCI deficiency protected mice from developing experimental autoimmune encephalomyelitis and experimental T cell transfer colitis. Our results thus show a critical role for de novo sphingolipid biosynthetic pathway in shaping adaptive immune responses with implications in autoimmune diseases.

DOI: https://doi.org/10.1126/sciadv.adk1045

Cell. 2024 Apr 17. pii: S0092-8674(24)00397-0. [Epub ahead of print]

Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis.

Zhi Zong, Feng Xie, Shuai Wang, Xiaojin Wu, Zhenyu Zhang, Bing Yang, Fangfang Zhou.

Lysine lactylation is a post-translational modification that links cellular metabolism to protein function. Here, we find that AARS1 functions as a lactate sensor that mediates global lysine lacylation in tumor cells. AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue. Proteomics studies reveal a large number of AARS1 targets, including p53 where lysine 120 and lysine 139 in the DNA binding domain are lactylated. Generation and utilization of p53 variants carrying constitutively lactylated lysine residues revealed that AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation. AARS1 expression and p53 lacylation correlate with poor prognosis among cancer patients carrying wild type p53. β-alanine disrupts lactate binding to AARS1, reduces p53 lacylation, and mitigates tumorigenesis in animal models. We propose that AARS1 contributes to tumorigenesis by coupling tumor cell metabolism to proteome alteration.

Keywords: AARS1; LLPS; alanyl-tRNA synthetase 1; lactate; lactylation; lactyltransferase; liquid-liquid phase separation; p53; tumor progression; β-alanine

DOI: https://doi.org/10.1016/j.cell.2024.04.002