TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
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IF 3.4
Shan Hu,Guiqing Liu,Haiyan Xiang,Jun Shao,Wanqi Lan,Chao Luo,Yonggang Shi,Wu Liu,Congcong Li,Yanhua Tang,Juesheng Yang
Background Myocardial ischemia-reperfusion (I/R) is pivotal in myocardial infarction. Transient receptor potential melastatin 7 (TRPM7) plays an instrumental role in sustaining intracellular ion concentration and osmotic pressure. This study aimed to explore the function and mechanism of TRPM7 in the myocardial I/R model. Methods AC16 cardiomyocytes were exposed to hypoxia for 4 h and reoxygenated for 2, 4, 6, 8, and 12 h (H/R1 to H/R5). Cellular functions were evaluated using the MTT assay and flow cytometry. Protein expression was assessed by western blotting. Metabolic variations were detected with pyruvate and lactate kits. Chromatin Immunoprecipitation assays elucidated transcriptional regulation. A myocardial I/R model was constructed, and a TRPM7 inhibitor was administered in the corresponding group; immunohistochemistry, HE staining, and TUNEL assays were conducted for tissue-level detection. Results The findings revealed a significant decline in cell survival rates, and an increase in apoptosis and TRPM7 expression of AC16 cardiomyocytes under hypoxia/reoxygenation (H/R) conditions, with peak effects in the H/R3 condition. Silencing TRPM7 significantly reversed H/R-induced Ca 2+ influx, cell survival rates, and apoptosis. Metabolic analyses indicated an upregulation of glycolysis in AC16 cardiomyocytes under the early stage of H/R, evidenced by elevated glycolysis-related proteins, pyruvate, and lactate levels, and the glycolytic inhibitor 2-Deoxy- d -glucose (2-DG) inhibited the expression of TRPM7. Subsequent assays showed that H/R-induced glycolysis promoted TRPM7 transcription through histone lactylation, a finding corroborated by the in vivo I/R model. Conclusions This study highlighted that histone lactylation could be a potential therapeutic target for modulating TRPM7 expression and mitigating I/R injury.
研究领域:
心血管病学
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分子生物学
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病理学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CELL
·
2024
·
IF 45.5
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.
研究领域:
癌症生物学
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分子生物学
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细胞代谢
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蛋白质组学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Jiaxing Huang,Xiaotang Wang,Na Li,Wei Fan,Xingran Li,Qian Zhou,Jiangyi Liu,Wanqian Li,Zhi Zhang,Xiaoyan Liu,Shuhao Zeng,Hui Yang,Meng Tian,Peizeng Yang,Shengping Hou
Activated microglia in the retina are essential for the development of autoimmune uveitis. Yin-Yang 1 (YY1) is an important transcription factor that participates in multiple inflammatory and immune-mediated diseases. Here, an increased YY1 lactylation in retinal microglia within in the experimental autoimmune uveitis (EAU) group is observed. YY1 lactylation contributed to boosting microglial activation and promoting their proliferation and migration abilities. Inhibition of lactylation suppressed microglial activation and attenuated inflammation in EAU. Mechanistically, cleavage under targets & tagmentation （CUT&Tag） analysis revealed that YY1 lactylation promoted microglial activation by regulating the transcription of a set of inflammatory genes, including STAT3, CCL5, IRF1, IDO1 , and SEMA4D . In addition, p300 is identified as the writer of YY1 lactylation. Inhibition of p300 decreased YY1 lactylation and suppressed microglial inflammation in vivo and in vitro. Collectively, the results showed that YY1 lactylation promoted microglial dysfunction in autoimmune uveitis by upregulating inflammatory cytokine secretion and boosting cell migration and proliferation. Therapeutic effects can be achieved by targeting the lactate/p300/YY1 lactylation/inflammatory genes axis.
研究领域:
免疫学
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神经科学
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分子生物学
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眼科学
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产品关联
DOI
PubMed
高影响因子
iScience
·
2022
·
IF 6.107
Dawei Yang,Jie Yin,Liuqun Shan,Xingling Yi,Wei Zhang,Yongbin Ding
Summary Cancer cells tend to utilize aerobic glycolysis to generate energy and metabolites; the end product of aerobic glycolysis is lactate, which promotes lysine lactylation (Kla). Kla is a newly discovered histone post-translational modification (PTM) that plays important roles in regulating gene expression. However, Kla in non-histone mammalian proteins is unclear. Here, a comprehensive analysis of lactylated proteins in gastric cancer AGS cells was conducted. There were 2375 Kla sites found in 1014 proteins. Interestingly, KEGG pathway analysis showed that these proteins were significantly enriched in spliceosome function. In addition, Kla was more abundant in gastric tumors than in adjacent tissues, and high levels of Kla in gastric tumors were associated with poor prognosis. These results suggest that Kla could be a prognostic marker in gastric cancer. This lysine lactylome analysis in gastric cancer cells, the first of its kind, provides a valuable foundation for further studies of Kla.
研究领域:
癌症生物学
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蛋白质组学
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分子生物学
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生物化学
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DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2024
·
IF 3.3
Jun Yan,Yunfei Zhou,Jianwen Xu,Yihong Dong,Xun Yang,Xinxin Yang,Aodi Wu,Shuyuan Chang,Yumeng Wang,Qingxin Zhang,Tomii Ayaka,Lei Yu,Liuyang Zhao,Hongxue Meng,Dabin Liu
Lactylation is an emerging pathogenesis of hepatocellular carcinoma (HCC). However, the underlying mechanisms and biological significance remain poorly understood. The Carbonic anhydrase III (CA3) gene, previously defined as a binding protein of SQLE and involved in the NAFLD disease, has now been identified as a novel tumor suppressor in HCC. mRNA expression of CA3 is associated with a favorable prognosis and negatively correlated with serum lactate levels, whereas CA3 protein expression does not correlate with patient prognosis or serum lactate levels, suggested there has lactate-related post-translational modification of CA3 in HCC. Overexpression of CA3 induces cell apoptosis, thereby reducing intracellular reactive oxygen stress (ROS) through the inhibition of DUOX2 expression. The decreased lactylation level of CA3 protein at the K36 residues, induced by SQLE, results in the loss of the anti-cancer effect of CA3. Together, this study has demonstrated that CA3 is a novel tumor suppressor in HCC, and delactylation of CA3 represents a newly identified mechanism by which HCC cells evade growth suppressors.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
Brain Sciences
·
2024
·Vol. 14
·期 4
·327
·
IF 2.7
Yuhan Wu,Hui Hu,Weiwei Liu,Yun Zhao,Fang Xie,Zhaowei Sun,Ling Zhang,Huafeng Dong,Xue Wang,Lingjia Qian
Lactate has emerged as a key player in regulating neural functions and cognitive processes. Beyond its function as an energy substrate and signal molecule, recent research has revealed lactate to serve as an epigenetic regulator in the brain. However, the molecular mechanisms by which lactate regulates spatial memory and its role in the prevention of cognitive disorders remain unclear. Herein, we injected L-lactate (10 μmol/kg/d for 6 d) into the mouse’s hippocampus, followed by the Morris water maze (MWM) test and molecular analyses. Improved spatial memory performances were observed in mice injected with lactate. Besides, lactate upregulated the expression of synaptic proteins post-synaptic density 95 (PSD95), synaptophysin (SYP), and growth associated protein 43 (GAP43) in hippocampal tissues and HT22 cells, suggesting a potential role in synaptic transmission and memory formation. The facilitative role of monocarboxylate transporter 2 (MCT2), a neuron-specific lactate transporter, in this process was confirmed, as MCT2 antagonists attenuated the lactate-induced upregulation of synaptic proteins. Moreover, lactate induced protein lactylation, a post-translational modification, which could be suppressed by MCT2 inhibition. RNA sequencing of lactated-injected hippocampal tissues revealed a comprehensive gene expression profile influenced by lactate, with significant changes in genes associated with transcriptional progress. These data demonstrate that hippocampal lactate injection enhances spatial memory in mice, potentially through the upregulation of synaptic proteins and induction of protein lactylation, with MCT2 playing a crucial role in these processes. Our findings shed light on the multi-faceted role of lactate in neural function and memory regulation, opening new avenues for therapeutic interventions targeting cognitive disorders.
研究领域:
神经科学
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认知科学
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分子生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2024
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IF 4.4
Jingyi Li,Ziyu Chen,Mingming Jin,Xuefeng Gu,Yuhan Wang,Gang Huang,Weiming Zhao,Changlian Lu
Lactylation, a newly identified post-translational modification, is uncertain in its implication in triple-negative breast cancer (TNBC). In this study, we analyzed 60 TNBC samples using immunohistochemical staining and revealed elevated levels of pan-lactylated proteins and specific histone H4K12 lactylation in tumor tissues, correlating with TNBC progression. Lactate exposure in TNBC cell lines significantly induced lysine lactylation at the H4K12 site, leading to alterations in gene profiles and reduced apoptosis. These effects were attenuated by DCA or sodium Oxamate, inhibitors of endogenous lactate production. Gene sequencing showed an increase in Schlafen 5 (SLFN5) expression in TNBC cells treated with Oxamate, contrasting with the effects of lactate exposure. Analysis of TNBC tissues showed a negative correlation between H4K12 lactylation and SLFN5 protein levels. Overexpression of SLFN5 countered the effects of lactate on apoptosis and tumor growth, highlighting its pivotal role in TNBC malignancy. CUT&Tag sequencing indicated that lactylated H4K12 potentially binds to the SLFN5 promoter region. Luciferase reporter assays further verified that lactate-induced suppression of SLFN5 promoter activity is mediated by wild-type H4K12, but not by its R or A mutants, verified by both in vitro and in vivo apoptosis detection in response to lactate and Oxamate stimulation. These results establish that H4K12 lactylation, induced by lactate in TNBC cells, specifically suppresses SLFN5 expression, contributing to TNBC malignancy. Our findings illuminate a critical histone lactylation-dependent carcinogenic pathway in TNBC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
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