bims-meprid 2024-02-04 papers

Mol Metab. 2024 Jan 31. pii: S2212-8778(24)00019-X. [Epub ahead of print] 101888

Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation.

Marissa N Trujillo, Erin Q Jennings, Emely A Hoffman, Hao Zhang, Aiden M Phoebe, Grace E Mastin, Naoya Kitamura, Julie A Reisz, Emily Megill, Daniel Kantner, Mariola M Marcinkiewicz, Shannon M Twardy, Felicidad Lebario, Eli Chapman, Rebecca L McCullough, Angelo D'Alessandro, Nathaniel W Snyder, Darren A Cusanovich, James J Galligan.

Chronic, systemic inflammation is a pathophysiological manifestation of metabolic disorders. Inflammatory signaling leads to elevated glycolytic flux and a metabolic shift towards aerobic glycolysis and lactate generation. This rise in lactate corresponds with increased generation of lactoylLys modifications on histones, mediating transcriptional responses to inflammatory stimuli. Lactoylation is also generated through a non-enzymatic S-to-N acyltransfer from the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Here, we report a regulatory role for LGSH in mediating histone lactoylation and inflammatory signaling. In the absence of the primary LGSH hydrolase, glyoxalase 2 (GLO2), RAW264.7 macrophages display significant elevations in LGSH and histone lactoylation with a corresponding potentiation of the inflammatory response when exposed to lipopolysaccharides. An analysis of chromatin accessibility shows that lactoylation is associated with more compacted chromatin than acetylation in an unstimulated state; upon stimulation, however, regions of the genome associated with lactoylation become markedly more accessible. Lastly, we demonstrate a spontaneous S-to-S acyltransfer of lactate from LGSH to CoA, yielding lactoyl-CoA. This represents the first known mechanism for the generation of this metabolite. Collectively, these data suggest that LGSH, and not intracellular lactate, is the primary driving factor facilitating histone lactoylation and a major contributor to inflammatory signaling.

Keywords: Metabolism; glyoxalase; inflammation; lactate; post-translational modification

DOI: https://doi.org/10.1016/j.molmet.2024.101888

Cell Rep. 2024 Jan 30. pii: S2211-1247(24)00052-4. [Epub ahead of print]43(2): 113724

p53 promotes antiviral innate immunity by driving hexosamine metabolism.

Wenjun Xia, Peng Jiang.

The tumor suppressor p53 controls cell fate decisions and prevents malignant transformation, but its functions in antiviral immunity remain unclear. Here, we demonstrate that p53 metabolically promotes antiviral innate immune responses to RNA viral infection. p53-deficient macrophages or mice display reduced expression of glutamine fructose-6-phosphate amidotransferase 2 (GFPT2), a key enzyme of the hexosamine biosynthetic pathway (HBP). Through transcriptional upregulation of GFPT2, p53 drives HBP activity and de novo synthesis of UDP-GlcNAc, which in turn leads to the O-GlcNAcylation of mitochondrial antiviral signaling protein (MAVS) and UBX-domain-containing protein 1 (UBXN1) during virus infection. Moreover, O-GlcNAcylation of UBXN1 blocks its interaction with MAVS, thereby further liberating MAVS for tumor necrosis factor receptor-associated factor 3 binding to activate TANK-binding kinase 1-interferon (IFN) regulatory factor 3 signaling cascades and IFN-β production. Genetic or pharmaceutical inhibition of GFPT efficiently reduces MAVS activation and abrogates the antiviral innate immunity promoted by p53 in vitro and in vivo. Our findings reveal that p53 drives HBP activity and O-GlcNAcylation of UBXN1 and MAVS to enhance IFN-β-mediated antiviral innate immunity.

Keywords: CP: Cell biology; CP: Immunology; O-GlcNAcylation; UBXN1-MAVS signaling; antiviral innate immunity; hexosamine metabolism; tumor suppressor p53

DOI: https://doi.org/10.1016/j.celrep.2024.113724

Sci Adv. 2024 Feb 02. 10(5): eadj9479

Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.

Adam G Maynard, Nancy K Pohl, Annabel P Mueller, Boryana Petrova, Alan Y L Wong, Peng Wang, Andrew J Culhane, Jeannette R Brook, Leah M Hirsch, Ngoc Hoang, Orville Kirkland, Tatum Braun, Sarah Ducamp, Mark D Fleming, Hojun Li, Naama Kanarek.

Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the inhibitor SHIN1, and by AICAR supplementation. Mechanistically, the metabolically driven differentiation is independent of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine 5'-monophosphate-activated protein kinase (AMPK) and is instead mediated by protein kinase C. Our findings suggest that folate deprivation-induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate deficiency-induced anemia.

DOI: https://doi.org/10.1126/sciadv.adj9479

Cancer Res. 2024 Jan 29.

Lactate utilization enables metabolic escape to confer resistance to BET inhibition in acute myeloid leukemia.

Andrew J Monteith, Haley E Ramsey, Alexander J Silver, Donovan Brown, Dalton Greenwood, Brianna N Smith, Ashley D Wise, Juan Liu, Sarah D Olmstead, Jackson Watke, Maria P Arrate, Agnieszka E Gorska, Londa Fuller, Jason W Locasale, Matthew C Stubbs, Jeffrey C Rathmell, Michael R Savona.

Impairing the BET-family co-activator BRD4 with small molecule inhibitors (BETi) showed encouraging pre-clinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0291

bioRxiv. 2024 Jan 25. pii: 2024.01.11.575111. [Epub ahead of print]

Short-chain fatty acids propionate and butyrate control growth and differentiation linked to cellular metabolism.

Michael Nshanian, Benjamin S Geller, Joshua J Gruber, Faye Chleilat, Jeannie Marie Camarillo, Neil L Kelleher, Yingming Zhao, Michael P Snyder.

The short-chain fatty acids (SCFA) propionate and butyrate are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. In order to better understand the function of these modifications we used ChIP-seq to map the genome-wide location of four short-chain acyl histone marks H3K18pr/bu and H4K12pr/bu in treated and untreated colorectal cancer (CRC) and normal cells, as well as in mouse intestines in vivo . We correlate these marks with open chromatin regions along with gene expression to access the function of the target regions. Our data demonstrate that propionate and butyrate act as promoters of growth, differentiation as well as ion transport. We propose a mechanism involving direct modification of specific genomic regions, resulting in increased chromatin accessibility, and in case of butyrate, opposing effects on the proliferation of normal versus CRC cells.

DOI: https://doi.org/10.1101/2024.01.11.575111