Pub Date : 2024-12-05DOI: 10.1016/j.cmet.2024.11.005
Ruilong Liu, Xuelian Ren, Yae Eun Park, Huixu Feng, Xinlei Sheng, Xiaohan Song, Roya AminiTabrizi, Hardik Shah, Lingting Li, Yu Zhang, Kalil G. Abdullah, Sarah Dubois-Coyne, Hening Lin, Philip A. Cole, Ralph J. DeBerardinis, Samuel K. McBrayer, He Huang, Yingming Zhao
Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma.
{"title":"Nuclear GTPSCS functions as a lactyl-CoA synthetase to promote histone lactylation and gliomagenesis","authors":"Ruilong Liu, Xuelian Ren, Yae Eun Park, Huixu Feng, Xinlei Sheng, Xiaohan Song, Roya AminiTabrizi, Hardik Shah, Lingting Li, Yu Zhang, Kalil G. Abdullah, Sarah Dubois-Coyne, Hening Lin, Philip A. Cole, Ralph J. DeBerardinis, Samuel K. McBrayer, He Huang, Yingming Zhao","doi":"10.1016/j.cmet.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.11.005","url":null,"abstract":"Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"109 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-03DOI: 10.1016/j.cmet.2024.10.022
Andreas Carlström, Martin Ott
Mitochondrial energy conversion supplies cellular energy but can also provide heat in brown adipose tissue (BAT). In a recent study, Shin and Latorre-Muro et al.1 show that respiratory supercomplexes in BAT are remodeled during cold to provide a tighter coupling, revealing a novel, physiologically important role for these supramolecular assemblies.
{"title":"Mitochondrial respiratory supercomplexes gear up for heat generation in brown adipose tissue","authors":"Andreas Carlström, Martin Ott","doi":"10.1016/j.cmet.2024.10.022","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.022","url":null,"abstract":"Mitochondrial energy conversion supplies cellular energy but can also provide heat in brown adipose tissue (BAT). In a recent study, Shin and Latorre-Muro et al.<span><span><sup>1</sup></span></span> show that respiratory supercomplexes in BAT are remodeled during cold to provide a tighter coupling, revealing a novel, physiologically important role for these supramolecular assemblies.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"41 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-26DOI: 10.1016/j.cmet.2024.10.021
Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E. Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M. Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Umberto De Marchi
Mitochondrial calcium (mtCa2+) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa2+ uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa2+ uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa2+ uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa2+ uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.
{"title":"Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance","authors":"Gaia Gherardi, Anna Weiser, Flavien Bermont, Eugenia Migliavacca, Benjamin Brinon, Guillaume E. Jacot, Aurélie Hermant, Mattia Sturlese, Leonardo Nogara, Filippo Vascon, Agnese De Mario, Andrea Mattarei, Emma Garratt, Mark Burton, Karen Lillycrop, Keith M. Godfrey, Laura Cendron, Denis Barron, Stefano Moro, Bert Blaauw, Umberto De Marchi","doi":"10.1016/j.cmet.2024.10.021","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.021","url":null,"abstract":"Mitochondrial calcium (mtCa<sup>2+</sup>) uptake via the mitochondrial calcium uniporter (MCU) couples calcium homeostasis and energy metabolism. mtCa<sup>2+</sup> uptake via MCU is rate-limiting for mitochondrial activation during muscle contraction, but its pathophysiological role and therapeutic application remain largely uncharacterized. By profiling human muscle biopsies, patient-derived myotubes, and preclinical models, we discovered a conserved downregulation of mitochondrial calcium uniporter regulator 1 (MCUR1) during skeletal muscle aging that associates with human sarcopenia and impairs mtCa<sup>2+</sup> uptake and mitochondrial respiration. Through a screen of 5,000 bioactive molecules, we identify the natural polyphenol oleuropein as a specific MCU activator that stimulates mitochondrial respiration via mitochondrial calcium uptake 1 (MICU1) binding. Oleuropein activates mtCa<sup>2+</sup> uptake and energy metabolism to enhance endurance and reduce fatigue in young and aged mice but not in muscle-specific MCU knockout (KO) mice. Our work demonstrates that impaired mtCa<sup>2+</sup> uptake contributes to mitochondrial dysfunction during aging and establishes oleuropein as a novel food-derived molecule that specifically targets MCU to stimulate mitochondrial bioenergetics and muscle performance.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"26 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The effect of the serine/glycine-free diet (−SG diet) on colorectal cancer (CRC) remains unclear; meanwhile, programmed death-1 (PD-1) inhibitors are less effective for most CRC patients. Here, we demonstrate that the −SG diet inhibits CRC growth and promotes the accumulation of cytotoxic T cells to enhance antitumor immunity. Additionally, we also identified the lactylation of programmed death-ligand 1 (PD-L1) in tumor cells as a mechanism of immune evasion during cytotoxic T cell-mediated antitumor responses, and blocking the PD-1/PD-L1 signaling pathway is able to rejuvenate the function of CD8+ T cells recruited by the −SG diet, indicating the potential of combining the −SG diet with immunotherapy. We conducted a single-arm, phase I study (ChiCTR2300067929). The primary outcome suggests that the −SG diet is feasible and safe for regulating systemic immunity. Secondary outcomes include patient tolerability and potential antitumor effects. Collectively, our findings highlight the promising therapeutic potential of the −SG diet for treating solid tumors.
无丝氨酸/甘氨酸饮食（-SG 饮食）对结直肠癌（CRC）的影响仍不清楚；同时，程序性死亡-1（PD-1）抑制剂对大多数 CRC 患者的疗效较差。在这里，我们证明了 -SG 饮食能抑制 CRC 的生长，并促进细胞毒性 T 细胞的积累，从而增强抗肿瘤免疫力。此外，我们还发现肿瘤细胞中程序性死亡配体1（PD-L1）的乳化是细胞毒性T细胞介导的抗肿瘤反应中的免疫逃避机制，而阻断PD-1/PD-L1信号通路能够恢复-SG饮食所招募的CD8+ T细胞的功能，这表明-SG饮食与免疫疗法的结合具有潜力。我们进行了一项单臂 I 期研究（ChiCTR2300067929）。主要结果表明，-SG 饮食在调节全身免疫力方面是可行且安全的。次要结果包括患者的耐受性和潜在的抗肿瘤效果。总之，我们的研究结果凸显了 -SG 饮食治疗实体瘤的巨大潜力。
{"title":"Dual impacts of serine/glycine-free diet in enhancing antitumor immunity and promoting evasion via PD-L1 lactylation","authors":"Huan Tong, Zedong Jiang, Linlin Song, Keqin Tan, Xiaomeng Yin, Chengyuan He, Juan Huang, Xiaoyue Li, Xiaofan Jing, Hong Yun, Guangqi Li, Yunuo Zhao, Qianlong Kang, Yuhao Wei, Renwei Li, Zhiwen Long, Jun Yin, Qiang Luo, Xiao Liang, Yanzhi Wan, Xuelei Ma","doi":"10.1016/j.cmet.2024.10.019","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.019","url":null,"abstract":"The effect of the serine/glycine-free diet (−SG diet) on colorectal cancer (CRC) remains unclear; meanwhile, programmed death-1 (PD-1) inhibitors are less effective for most CRC patients. Here, we demonstrate that the −SG diet inhibits CRC growth and promotes the accumulation of cytotoxic T cells to enhance antitumor immunity. Additionally, we also identified the lactylation of programmed death-ligand 1 (PD-L1) in tumor cells as a mechanism of immune evasion during cytotoxic T cell-mediated antitumor responses, and blocking the PD-1/PD-L1 signaling pathway is able to rejuvenate the function of CD8+ T cells recruited by the −SG diet, indicating the potential of combining the −SG diet with immunotherapy. We conducted a single-arm, phase I study (ChiCTR2300067929). The primary outcome suggests that the −SG diet is feasible and safe for regulating systemic immunity. Secondary outcomes include patient tolerability and potential antitumor effects. Collectively, our findings highlight the promising therapeutic potential of the −SG diet for treating solid tumors.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"18 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1016/j.cmet.2024.10.020
Elise J. Needham, Janne R. Hingst, Johan D. Onslev, Alexis Diaz-Vegas, Magnus R. Leandersson, Hannah Huckstep, Jonas M. Kristensen, Kohei Kido, Erik A. Richter, Kurt Højlund, Benjamin L. Parker, Kristen Cooke, Guang Yang, Christian Pehmøller, Sean J. Humphrey, David E. James, Jørgen F.P. Wojtaszewski
Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters skeletal muscle signaling and how exercise partially counteracts this effect. We measured parallel phenotypes and phosphoproteomes of insulin-resistant (IR) and insulin-sensitive (IS) men as they responded to exercise and insulin (n = 19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Insulin resistance involves selective and time-dependent alterations to signaling, including reduced insulin-stimulated mTORC1 and non-canonical signaling responses. Prior exercise promotes insulin sensitivity even in IR individuals by “priming” a portion of insulin signaling prior to insulin infusion. This includes MINDY1 S441, which we show is an AKT substrate. We found that MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signaling alterations in IR skeletal muscle and identifies MINDY1 as a regulator of insulin action.
{"title":"Personalized phosphoproteomics of skeletal muscle insulin resistance and exercise links MINDY1 to insulin action","authors":"Elise J. Needham, Janne R. Hingst, Johan D. Onslev, Alexis Diaz-Vegas, Magnus R. Leandersson, Hannah Huckstep, Jonas M. Kristensen, Kohei Kido, Erik A. Richter, Kurt Højlund, Benjamin L. Parker, Kristen Cooke, Guang Yang, Christian Pehmøller, Sean J. Humphrey, David E. James, Jørgen F.P. Wojtaszewski","doi":"10.1016/j.cmet.2024.10.020","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.020","url":null,"abstract":"Type 2 diabetes is preceded by a defective insulin response, yet our knowledge of the precise mechanisms is incomplete. Here, we investigate how insulin resistance alters skeletal muscle signaling and how exercise partially counteracts this effect. We measured parallel phenotypes and phosphoproteomes of insulin-resistant (IR) and insulin-sensitive (IS) men as they responded to exercise and insulin (<em>n</em> = 19, 114 biopsies), quantifying over 12,000 phosphopeptides in each biopsy. Insulin resistance involves selective and time-dependent alterations to signaling, including reduced insulin-stimulated mTORC1 and non-canonical signaling responses. Prior exercise promotes insulin sensitivity even in IR individuals by “priming” a portion of insulin signaling prior to insulin infusion. This includes MINDY1 S441, which we show is an AKT substrate. We found that MINDY1 knockdown enhances insulin-stimulated glucose uptake in rat myotubes. This work delineates the signaling alterations in IR skeletal muscle and identifies MINDY1 as a regulator of insulin action.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"1 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1016/j.cmet.2024.10.018
Etienne Mouisel, Anaïs Bodon, Christophe Noll, Stéphanie Cassant-Sourdy, Marie-Adeline Marques, Remy Flores-Flores, Elodie Riant, Camille Bergoglio, Pierre Vezin, Sylvie Caspar-Bauguil, Camille Fournes-Fraresso, Geneviève Tavernier, Khalil Acheikh Ibn Oumar, Pierre Gourdy, Denis P. Blondin, Pierre-Damien Denechaud, André C. Carpentier, Dominique Langin
Long-chain fatty acids (FAs) are the major substrates fueling brown adipose tissue (BAT) thermogenesis. Investigation of mouse models has previously called into question the contribution of brown adipocyte intracellular lipolysis to cold-induced non-shivering thermogenesis. Here, we determined the role of the lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in BAT thermogenesis. Brown fat from mice with inducible brown-adipocyte-specific deletion of ATGL and HSL (BAHKO) is hypertrophied with increased lipid droplet size and preserved mitochondria area and density. Maintenance of body temperature during cold exposure is compromised in BAHKO mice in the fasted but not in the fed state. This altered response to cold is observed in various thermal and nutritional conditions. Positron emission tomography-computed tomography using [11C]-acetate and [11C]-palmitate shows abolished cold-induced BAT oxidative activity and impaired FA metabolism in BAHKO mice. Our findings show that brown adipocyte intracellular lipolysis is required for BAT thermogenesis.
长链脂肪酸（FA）是促进棕色脂肪组织（BAT）产热的主要底物。对小鼠模型的研究曾对棕色脂肪细胞内脂肪分解对寒冷诱导的非颤抖性产热的贡献提出过质疑。在这里，我们确定了脂肪分解酶--脂肪甘油三酯脂肪酶（ATGL）和激素敏感性脂肪酶（HSL）在BAT产热中的作用。诱导性棕色脂肪细胞特异性缺失 ATGL 和 HSL（BAHKO）的小鼠棕色脂肪肥厚，脂滴体积增大，线粒体面积和密度保持不变。BAHKO小鼠在空腹状态下，但在进食状态下，寒冷暴露时的体温维持受到影响。这种对寒冷反应的改变在各种热和营养条件下都能观察到。使用[11C]-乙酸酯和[11C]-棕榈酸酯进行的正电子发射断层扫描-计算机断层扫描显示，BAHKO 小鼠冷诱导的 BAT 氧化活性消失，FA 代谢受损。我们的研究结果表明，棕色脂肪细胞内脂肪分解是 BAT 产热所必需的。
{"title":"Cold-induced thermogenesis requires neutral-lipase-mediated intracellular lipolysis in brown adipocytes","authors":"Etienne Mouisel, Anaïs Bodon, Christophe Noll, Stéphanie Cassant-Sourdy, Marie-Adeline Marques, Remy Flores-Flores, Elodie Riant, Camille Bergoglio, Pierre Vezin, Sylvie Caspar-Bauguil, Camille Fournes-Fraresso, Geneviève Tavernier, Khalil Acheikh Ibn Oumar, Pierre Gourdy, Denis P. Blondin, Pierre-Damien Denechaud, André C. Carpentier, Dominique Langin","doi":"10.1016/j.cmet.2024.10.018","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.018","url":null,"abstract":"Long-chain fatty acids (FAs) are the major substrates fueling brown adipose tissue (BAT) thermogenesis. Investigation of mouse models has previously called into question the contribution of brown adipocyte intracellular lipolysis to cold-induced non-shivering thermogenesis. Here, we determined the role of the lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in BAT thermogenesis. Brown fat from mice with inducible brown-adipocyte-specific deletion of ATGL and HSL (BAHKO) is hypertrophied with increased lipid droplet size and preserved mitochondria area and density. Maintenance of body temperature during cold exposure is compromised in BAHKO mice in the fasted but not in the fed state. This altered response to cold is observed in various thermal and nutritional conditions. Positron emission tomography-computed tomography using [<sup>11</sup>C]-acetate and [<sup>11</sup>C]-palmitate shows abolished cold-induced BAT oxidative activity and impaired FA metabolism in BAHKO mice. Our findings show that brown adipocyte intracellular lipolysis is required for BAT thermogenesis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"11 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142670681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-18DOI: 10.1016/j.cmet.2024.10.015
Rongxuan Zhu, Xianglai Ye, Xiaotong Lu, Liwei Xiao, Ming Yuan, Hong Zhao, Dong Guo, Ying Meng, Hongkuan Han, Shudi Luo, Qingang Wu, Xiaoming Jiang, Jun Xu, Zhonghui Tang, Yizhi Jane Tao, Zhimin Lu
Lactyl-coenzyme A (CoA)-dependent histone lysine lactylation impacts gene expression and plays fundamental roles in biological processes. However, mammalian lactyl-CoA synthetases and their regulation of histone lactylation have not yet been identified. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces extracellular signal-regulated kinase (ERK)-mediated S267 phosphorylation of acetyl-CoA synthetase 2 (ACSS2) and its subsequent nuclear translocation and complex formation with lysine acetyltransferase 2A (KAT2A). Importantly, ACSS2 functions as a bona fide lactyl-CoA synthetase and converts lactate to lactyl-CoA, which binds to KAT2A as demonstrated by a co-crystal structure analysis. Consequently, KAT2A acts as a lactyltransferase to lactylate histone H3, leading to the expression of Wnt/β-catenin, NF-κB, and PD-L1 and brain tumor growth and immune evasion. A combination treatment with an ACSS2-KAT2A interaction-blocking peptide and an anti-PD-1 antibody induces an additive tumor-inhibitory effect. These findings uncover ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, and the significance of the ACSS2-KAT2A coupling in gene expression and tumor development.
{"title":"ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion","authors":"Rongxuan Zhu, Xianglai Ye, Xiaotong Lu, Liwei Xiao, Ming Yuan, Hong Zhao, Dong Guo, Ying Meng, Hongkuan Han, Shudi Luo, Qingang Wu, Xiaoming Jiang, Jun Xu, Zhonghui Tang, Yizhi Jane Tao, Zhimin Lu","doi":"10.1016/j.cmet.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.015","url":null,"abstract":"Lactyl-coenzyme A (CoA)-dependent histone lysine lactylation impacts gene expression and plays fundamental roles in biological processes. However, mammalian lactyl-CoA synthetases and their regulation of histone lactylation have not yet been identified. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces extracellular signal-regulated kinase (ERK)-mediated S267 phosphorylation of acetyl-CoA synthetase 2 (ACSS2) and its subsequent nuclear translocation and complex formation with lysine acetyltransferase 2A (KAT2A). Importantly, ACSS2 functions as a bona fide lactyl-CoA synthetase and converts lactate to lactyl-CoA, which binds to KAT2A as demonstrated by a co-crystal structure analysis. Consequently, KAT2A acts as a lactyltransferase to lactylate histone H3, leading to the expression of Wnt/β-catenin, NF-κB, and PD-L1 and brain tumor growth and immune evasion. A combination treatment with an ACSS2-KAT2A interaction-blocking peptide and an anti-PD-1 antibody induces an additive tumor-inhibitory effect. These findings uncover ACSS2 and KAT2A as hitherto unidentified lactyl-CoA synthetase and lactyltransferase, respectively, and the significance of the ACSS2-KAT2A coupling in gene expression and tumor development.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"6 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-18DOI: 10.1016/j.cmet.2024.10.012
Ting Li, Yueyue Liu, Tianchi Duan, Chao Guo, Bin Liu, Xiuqiong Fu, Lu Wang, Xiaoyuan Wang, Xinyue Dong, Chennan Wang, Yalong Lu, Yu Wang, Lin Shi, Honglei Tian, Xingbin Yang
Oligosaccharides are conventionally recognized as “passersby” in the small intestine. However, our research has reframed this understanding by uncovering a new function of oligosaccharide stachyose, which binds hydrophobic residues of membranous HSP90β on small intestinal epithelial cells, thus reprograming the exosomal miRNA profile. CRISPR-Cas9-mediated HSP90β knockout abolished the accumulation of stachyose on cell membrane and its regulatory effects on these miRNAs. Notably, stachyose’s regulation on these miRNAs is independent of its prebiotic role, as evidenced by the observation of stachyose-altered fecal miRNAs in pseudo-germ-free mice. These stachyose-altered miRNAs further shaped colonic microbiome, especially harboring Lactobacillus in mice. Thereinto, miR-30a-5p that was downregulated (Log2FC < −2) in both mice and human feces following stachyose treatment could specifically suppress the growth of Lactobacillus reuteri. These findings build a new regulatory axis of stachyose-intestinal miRNAs-gut microbiota and unveil a previously unknown mechanism underlying the direct “talk” of oligosaccharides to intestine epithelium via membranous HSP90β.
{"title":"Nondigestible stachyose binds membranous HSP90β on small intestinal epithelium to regulate the exosomal miRNAs: A new function and mechanism","authors":"Ting Li, Yueyue Liu, Tianchi Duan, Chao Guo, Bin Liu, Xiuqiong Fu, Lu Wang, Xiaoyuan Wang, Xinyue Dong, Chennan Wang, Yalong Lu, Yu Wang, Lin Shi, Honglei Tian, Xingbin Yang","doi":"10.1016/j.cmet.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.012","url":null,"abstract":"Oligosaccharides are conventionally recognized as “passersby” in the small intestine. However, our research has reframed this understanding by uncovering a new function of oligosaccharide stachyose, which binds hydrophobic residues of membranous HSP90β on small intestinal epithelial cells, thus reprograming the exosomal miRNA profile. CRISPR-Cas9-mediated HSP90β knockout abolished the accumulation of stachyose on cell membrane and its regulatory effects on these miRNAs. Notably, stachyose’s regulation on these miRNAs is independent of its prebiotic role, as evidenced by the observation of stachyose-altered fecal miRNAs in pseudo-germ-free mice. These stachyose-altered miRNAs further shaped colonic microbiome, especially harboring <em>Lactobacillus</em> in mice. Thereinto, miR-30a-5p that was downregulated (Log<sub>2</sub>FC < −2) in both mice and human feces following stachyose treatment could specifically suppress the growth of <em>Lactobacillus reuteri</em>. These findings build a new regulatory axis of stachyose-intestinal miRNAs-gut microbiota and unveil a previously unknown mechanism underlying the direct “talk” of oligosaccharides to intestine epithelium via membranous HSP90β.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"10 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-18DOI: 10.1016/j.cmet.2024.10.007
Shen Li, Hongbo Liu, Hailong Hu, Eunji Ha, Praveena Prasad, Brenita C. Jenkins, Ujjalkumar Subhash Das, Sarmistha Mukherjee, Kyosuke Shishikura, Renming Hu, Daniel J. Rader, Liming Pei, Joseph A. Baur, Megan L. Matthews, Garret A. FitzGerald, Melanie R. McReynolds, Katalin Susztak
The understanding of cardiovascular-kidney-metabolic syndrome remains difficult despite recently performed large scale genome-wide association studies. Here, we identified beta-lactamase (LACTB), a novel gene whose expression is targeted by genetic variations causing kidney dysfunction and hyperlipidemia. Mice with LACTB deletion developed impaired glucose tolerance, elevated lipid levels, and increased sensitivity to kidney disease, while mice with tubule-specific overexpression of LACTB were protected from kidney injury. We show that LACTB is a novel mitochondrial protease cleaving and activating phospholipase A2 group VI (PLA2G6), a kidney-metabolic risk gene itself. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished the protective function of LACTB. Via mouse and human lipidomic studies, we show that LACTB and downstream PLA2G6 convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine and thereby regulate mitochondrial function and ferroptosis. In summary, we identify a novel gene and a core targetable pathway for kidney-metabolic disorders.
{"title":"Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome","authors":"Shen Li, Hongbo Liu, Hailong Hu, Eunji Ha, Praveena Prasad, Brenita C. Jenkins, Ujjalkumar Subhash Das, Sarmistha Mukherjee, Kyosuke Shishikura, Renming Hu, Daniel J. Rader, Liming Pei, Joseph A. Baur, Megan L. Matthews, Garret A. FitzGerald, Melanie R. McReynolds, Katalin Susztak","doi":"10.1016/j.cmet.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.007","url":null,"abstract":"The understanding of cardiovascular-kidney-metabolic syndrome remains difficult despite recently performed large scale genome-wide association studies. Here, we identified beta-lactamase (LACTB), a novel gene whose expression is targeted by genetic variations causing kidney dysfunction and hyperlipidemia. Mice with LACTB deletion developed impaired glucose tolerance, elevated lipid levels, and increased sensitivity to kidney disease, while mice with tubule-specific overexpression of LACTB were protected from kidney injury. We show that LACTB is a novel mitochondrial protease cleaving and activating phospholipase A2 group VI (PLA2G6), a kidney-metabolic risk gene itself. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished the protective function of LACTB. Via mouse and human lipidomic studies, we show that LACTB and downstream PLA2G6 convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine and thereby regulate mitochondrial function and ferroptosis. In summary, we identify a novel gene and a core targetable pathway for kidney-metabolic disorders.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"13 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-14DOI: 10.1016/j.cmet.2024.10.016
Jivani M. Gengatharan, Michal K. Handzlik, Zoya Y. Chih, Maureen L. Ruchhoeft, Patrick Secrest, Ethan L. Ashley, Courtney R. Green, Martina Wallace, Philip L.S.M. Gordts, Christian M. Metallo
Dietary fat drives the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), particularly through circulating cholesterol and triglyceride-rich lipoprotein remnants. Industrially produced trans-unsaturated fatty acids (TFAs) incorporated into food supplies significantly promote ASCVD. However, the molecular trafficking of TFAs responsible for this association is not well understood. Here, we demonstrate that TFAs are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT) and secreted from cells in vitro. Administering high-fat diets (HFDs) enriched in TFAs to Ldlr−/− mice accelerated hepatic very-low-density lipoprotein (VLDL) and sphingolipid secretion into circulation to promote atherogenesis compared with a cis-unsaturated fatty acid (CFA)-enriched HFD. SPT inhibition mitigated these phenotypes and reduced circulating atherogenic VLDL enriched in TFA-derived polyunsaturated sphingomyelin. Transcriptional analysis of human liver revealed distinct regulation of SPTLC2 versus SPTLC3 subunit expression, consistent with human genetic correlations in ASCVD, further establishing sphingolipid metabolism as a critical node mediating the progression of ASCVD in response to specific dietary fats.
{"title":"Altered sphingolipid biosynthetic flux and lipoprotein trafficking contribute to trans-fat-induced atherosclerosis","authors":"Jivani M. Gengatharan, Michal K. Handzlik, Zoya Y. Chih, Maureen L. Ruchhoeft, Patrick Secrest, Ethan L. Ashley, Courtney R. Green, Martina Wallace, Philip L.S.M. Gordts, Christian M. Metallo","doi":"10.1016/j.cmet.2024.10.016","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.10.016","url":null,"abstract":"Dietary fat drives the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), particularly through circulating cholesterol and triglyceride-rich lipoprotein remnants. Industrially produced <em>trans</em>-unsaturated fatty acids (TFAs) incorporated into food supplies significantly promote ASCVD. However, the molecular trafficking of TFAs responsible for this association is not well understood. Here, we demonstrate that TFAs are preferentially incorporated into sphingolipids by serine palmitoyltransferase (SPT) and secreted from cells <em>in vitro</em>. Administering high-fat diets (HFDs) enriched in TFAs to <em>Ldlr</em><sup><em>−/−</em></sup> mice accelerated hepatic very-low-density lipoprotein (VLDL) and sphingolipid secretion into circulation to promote atherogenesis compared with a <em>cis</em>-unsaturated fatty acid (CFA)-enriched HFD. SPT inhibition mitigated these phenotypes and reduced circulating atherogenic VLDL enriched in TFA-derived polyunsaturated sphingomyelin. Transcriptional analysis of human liver revealed distinct regulation of <em>SPTLC2</em> versus <em>SPTLC3</em> subunit expression, consistent with human genetic correlations in ASCVD, further establishing sphingolipid metabolism as a critical node mediating the progression of ASCVD in response to specific dietary fats.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"37 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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