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Lactate remodulates the OXPHOS of Tregs by inducing N-glycosylation in mitochondria via transcription and translocation of MGAT1

ABSTRACT: Proteomic data of control and lactate-treated Naive Treg and Memory Treg

ORGANISM(S): Homo Sapiens

SUBMITTER: Ling Lv

PROVIDER: PXD056590 | iProX | Fri Oct 04 00:00:00 BST 2024

REPOSITORIES: iProX

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Lactate supports Treg function and immune balance via MGAT1 effects on N-glycosylation in the mitochondria.

Zhou Jinren J Gu Jian J Qian Qufei Q Zhang Yigang Y Huang Tianning T Li Xiangyu X Liu Zhuoqun Z Shao Qing Q Liang Yuan Y Qiao Lei L Xu Xiaozhang X Chen Qiuyang Q Xu Zibo Z Li Yu Y Gao Ji J Pan Yufeng Y Wang Yiming Y O'Connor Roderick R Hippen Keli L KL Lu Ling L Blazar Bruce R BR

The Journal of clinical investigation 20240912 20

Current research reports that lactate affects Treg metabolism, although the precise mechanism has only been partially elucidated. In this study, we presented evidence demonstrating that elevated lactate levels enhanced cell proliferation, suppressive capabilities, and oxidative phosphorylation (OXPHOS) in human Tregs. The expression levels of Monocarboxylate Transporters 1/2/4 (MCT1/2/4) regulate intracellular lactate concentration, thereby influencing the varying responses observed in naive Tre ...[more]

PMID: 39264847

Similar Datasets

Lactate supports Treg function and immune balance via MGAT1 effects on N-glycosylation in the mitochondria.

Project description:Current research reports that lactate affects Treg metabolism, although the precise mechanism has only been partially elucidated. In this study, we presented evidence demonstrating that elevated lactate levels enhanced cell proliferation, suppressive capabilities, and oxidative phosphorylation (OXPHOS) in human Tregs. The expression levels of Monocarboxylate Transporters 1/2/4 (MCT1/2/4) regulate intracellular lactate concentration, thereby influencing the varying responses observed in naive Tregs and memory Tregs. Through mitochondrial isolation, sequencing, and analysis of human Tregs, we determined that α-1,3-Mannosyl-Glycoprotein 2-β-N-Acetylglucosaminyltransferase (MGAT1) served as the pivotal driver initiating downstream N-glycosylation events involving progranulin (GRN) and hypoxia-upregulated 1 (HYOU1), consequently enhancing Treg OXPHOS. The mechanism by which MGAT1 was upregulated in mitochondria depended on elevated intracellular lactate that promoted the activation of XBP1s. This, in turn, supported MGAT1 transcription as well as the interaction of lactate with the translocase of the mitochondrial outer membrane 70 (TOM70) import receptor, facilitating MGAT1 translocation into mitochondria. Pretreatment of Tregs with lactate reduced mortality in a xenogeneic graft-versus-host disease (GvHD) model. Together, these findings underscored the active regulatory role of lactate in human Treg metabolism through the upregulation of MGAT1 transcription and its facilitated translocation into the mitochondria.

| S-EPMC11473165 | biostudies-literature

Identification of genes regulated by L-lactate and by DL-lactate in Lactobacillus plantarum

Project description:L. plantarum is known to possess an L-lactate inducible lactate racemase activity (Goffin et al. 2005. J. Bacteriol. 187:6750). In the present study, microarrays were used in order to identify all genes that are up-regulated by L-lactate, but not by a racemic mixture of D- and L-lactate. A mutant of L. plantarum NCIMB8826 deficient for NAD-dependent L-lactate activity (TF101; Ferain et al. 1994. 176:596), and thus producing no L-lactate, was grown in MRS medium at 28Â°C until mid-exponential phase (OD600nm 0.75). The culture was then divided into 3 sub-cultures. Optically pure sodium L-lactate (200 mM) was added to the first sub-culture (TF101 + L-lac 200 mM). An equimolar mixture of sodium D- and L-lactate (100 mM each) was added to the second sub-culture (TF101 + L/D-lac 200 mM). The third sub-culture was not treated (TF101; reference sample). The three sub-cultures were further incubated at 28Â°C for 1h30 (a time known to be sufficient for induction of lactate racemase activity by L-lactate). Cells were harvested by centrifugation. Microarray data were used ot identify genes that are specifically induced by L-lactate (comparison of TF101 with TF101 + L-lac 200 mM), but not by DL-lactate (comparison of TF101 with T101 + L/D-lac 200 mM). There are no biological replicates.

2013-07-01 | E-GEOD-43518 | biostudies-arrayexpress

ACVR2A attenuation impacts lactate production and hyperglycolytic conditions attracting regulatory T cells in hepatocellular carcinoma

Project description:Although ACVR2A mutations are prevalent in non-viral hepatocellular carcinomas (HCC), the underlying mechanism remains unelucidated. Our molecular investigation reveals that ACVR2A impairment induces hyperglycolysis through the inactivation of the SMAD signaling pathway. Using syngeneic transplantation models and human clinical samples, we clarify that ACVR2A-deficient HCC cells produce and secrete lactate via the upregulation of LDHA and MCT4 expression levels, which promotes regulatory T (Treg) cell accumulation and then acquires resistance to immune checkpoint inhibitors. Remarkably, genetic knockdown and pharmacological inhibition of MCT4 ameliorate the high lactate milieu in ACVR2A-deficient HCC, resulting in the suppression of intratumoral Treg cell recruitment and the restoration of the sensitivity to PD-1 blockade. These findings furnish compelling evidence that lactate attenuates anti-tumor immunity, and that therapeutics targeting this pathway present a promising strategy for mitigating immunotherapy resistance in ACVR2A-deficient HCC.

2025-02-07 | GSE248922 | GEO

L-Chiral Hydrogel Accelerates Wound Healing via Lactate-Mediated RNF123 K57 Lactylation

Project description:Chronic wounds, characterized by delayed healing and persistent inflammation, represent a major clinical burden with limited effective therapies. Inspired by the stereoselective interactions in biological systems, we developed an L-chiral hydrogel composed of self-assembled helical nanofibers from L-histidine derivatives, which preferentially enriches lactate to promote wound repair. Compared to D-chiral and racemic hydrogels, the L-chiral hydrogel significantly accelerated wound closure in rat models, achieving nearly 90% healing by day 14 and reducing healing time to 16-17 days. Transcriptomic and metabolomic analyses revealed enhanced wound response pathways and elevated lactate levels in the L-chiral group. Mechanistically, enriched lactate induced K57 lactylation of RNF123, mediated by AARS1, altering RNF123 conformation and weakening its binding to UBAC1. This modification enhanced ubiquitination and processing of NF-κB p105 into p50, inhibiting the NF-κB pathway and promoting angiogenesis via enhanced endothelial cell migration, tube formation, and sprouting. Rescue experiments with lactate inhibitor Oxamate and exogenous lactate confirmed the lactate-dependent mechanism. This study not only demonstrates a drug-free chiral biomaterial for efficient wound healing but also unveils the molecular role of lactate-mediated lactylation in mechanoregulating inflammation and vascularization, offering new insights for regenerative medicine.

2025-10-17 | GSE308113 | GEO

Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism

Project description:Histone acetylation involves the transfer of a two-carbon unit to nucleus as embedded in low-concentration metabolites. We find that lactate, a high-concentration metabolic by-product, can be a major carbon source for histone acetylation, through oxidation-dependent metabolism. Both in cells and in purified nucleus, 13C3-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), the knockout of which abrogates the incorporation. Heterologous expression of nucleus-localized LDHA rescues the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces the acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence of the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing the disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism-epigenetics axis controlled by cell’s own or environmental status.

2023-11-21 | GSE235471 | GEO

Lactate sensing drives fungal immune evasion

Project description:Experiment Description RNA sequencing was performed on Candida albicans wild type cells (SC5314) grown to exponential phase on YNB Lactate, YNB Glucose, or YNB Glucose plus Lactate, and compared to exponential Candida albicans crz1 cells grown on YNB Glucose or YNB Glucose plus Lactate. Three independent experiments were performed.

2016-10-03 | E-MTAB-4579 | biostudies-arrayexpress

Lactate regulates cell differentiation of erythroid progenitor cells via histone lactylation modification [RNA-seq]

Project description:As a key metabolite of glycolysis, lactate plays important regulatory roles in a variety of biological events by regulating metabolic homeostasis and histone lactylation. However, the role of lactate and histone lactylation in human erythropoiesis remains unclear. Here, we explored the role of lactate in erythropoiesis by adding the glycolysis inhibitor 2-DG or exogenous lactate Na-La to decrease or increase intracellular lactate levels, respectively. The results showed that 2-DG treatment promoted erythroid progenitors differentiation, blocked cell cycle and reduced colony-forming ability of CFU-E. In contrast, Na-La delayed erythroid progenitors differentiation and promoted CFU-E colony formation. We also found that lactate levels directly regulated H3K14la and H3K18la intensity. Furthermore, CUT&Tag results showed that the lost H3K14la peaks after 2-DG treatment were mainly enriched in promoter region and were associated with cell cycle and division. RNA-seq results showed that gene expression pattern was dramatically altered after 2-DG treatment, and differentially expressed genes were enriched in cell cycle and division process. Integrated analysis of CUT&Tag and RNA-seq revealed that gene expression was regulated by H3K14la, and CCNB1, CFL1, CENPA, SKA2 and GNAI2 gene expression were verified by RT-qPCR. In conclusion, our study reveals that lactate affects the cell differentiation of early erythroid progenitors by regulating gene expression through histone lactylation.

2025-05-17 | GSE274169 | GEO

Lactate regulates cell differentiation of erythroid progenitor cells via histone lactylation modification [CUT&Tag]

2025-05-17 | GSE274165 | GEO

Identification of genes regulated by L-lactate and by DL-lactate in Lactobacillus plantarum

2013-07-01 | GSE43518 | GEO

Growth in minimal media with lactate

Project description:Growth to mid exponential phase in M9 minimal media supplemented with 0.5% lactate versus growth in rich LB media Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Media: M9 minimal media with 0.5% lactate Computed

2006-05-20 | E-GEOD-4875 | biostudies-arrayexpress

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