Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 109 - 128
Published: Jan. 1, 2025
Language: Английский
Cell Reports, Journal Year: 2023, Volume and Issue: 42(9), P. 113040 - 113040
Published: Aug. 24, 2023
The cyclic guanosine monophosphate adenosine synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in defending foreign pathogens and maintaining immune homeostasis. While substantial advances have been made understanding the metabolic changes that occur during macrophage activation, little is known about how these affect cGAS-STING axis. In this study, we identify 4-octyl itaconate (4-OI), derivative itaconate, inhibits activation cGAS-STING. Furthermore, show 4-OI cGAS-STING-related antiviral responses autoimmune inflammation. However, find endogenous does not indicating function differently. Mechanistically, directly alkylates STING at Cys91, blocking palmitoylation oligomerization. alkylation by represents another type post-translational modifications (PTMs) STING. Our findings reveal mechanism which regulated through provide insights into crosstalk between different kinds PTMs.
Language: Английский
Citations
42
Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(3), P. 498 - 510.e11
Published: Jan. 4, 2024
Language: Английский
Citations
30
Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(15)
Published: April 2, 2024
Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches reverse atherosclerotic are needed address rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which generated from tricarboxylic acid-intermediate cis-aconitate enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested therapeutic potential IRG1–itaconate axis human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), found IRG1 up-regulated in coronary lesions compared patient-matched healthy vasculature, and mouse models atherosclerosis, where it primarily expressed monocytes, macrophages, neutrophils. Global or hematopoietic Irg1 -deficiency mice increases atherosclerosis burden, macrophage lipid content, expression proatherosclerotic cytokine interleukin (IL)-1β. Mechanistically, absence increased accumulation, accelerated via neutrophil extracellular trap (NET) formation NET-priming NLRP3-inflammasome resulting IL-1β release. Conversely, supplementation –itaconate using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques reduced lesional levels mice. To investigate effects 4-OI humans, leveraged an ex vivo systems-immunology approach CVD drug discovery. CyTOF scRNA-seq peripheral blood mononuclear cells treated with plasma patients, showed attenuates proinflammatory phospho-signaling mediates anti-inflammatory rewiring populations. Our data highlight relevance pursuing as humans.
Language: Английский
Citations
25
Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: 35(7), P. 586 - 606
Published: March 5, 2024
Language: Английский
Citations
17
Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)
Published: Aug. 22, 2023
M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex using lipoate to generate nitroxyl (HNO). E2-associated is modified in NO-rich while E3 enzyme, also known as dihydrolipoamide (DLD), irreversibly inhibited. Mechanistically, show facilitates NO-mediated production of HNO, which interacts with thiols forming irreversible modifications including sulfinamide. In addition, reveal macrophage signature proteins reduction-resistant modifications, DLD, identify potential HNO targets. Consistently, DLD enzyme an HNO-dependent manner at Cys477 Cys484, molecular modeling mutagenesis these impair formation homodimers. conclusion, our work demonstrates produced physiologically. Moreover, dependent on lipoate-rich facilitating are critical NO-dependent metabolic rewiring.
Language: Английский
Citations
22
Nature Metabolism, Journal Year: 2024, Volume and Issue: 6(9), P. 1661 - 1667
Published: July 26, 2024
Language: Английский
Citations
12
Food Bioscience, Journal Year: 2024, Volume and Issue: 59, P. 103855 - 103855
Published: March 5, 2024
Language: Английский
Citations
11
Developmental Cell, Journal Year: 2024, Volume and Issue: 59(21), P. 2807 - 2817.e8
Published: Aug. 7, 2024
Language: Английский
Citations
9
Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: unknown
Published: Oct. 1, 2024
Language: Английский
Citations
9
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 2, 2025
Abstract Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid endogenously synthesized via tricarboxylic (TCA) downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little known about the turnover rate itaconate in circulation, kinetics its degradation, broader consequences on metabolism. By combining mass spectrometry vivo 13 C tracing, we demonstrate rapidly eliminated from plasma, excreted urine, fuels TCA cycle specifically liver kidneys. These studies further revealed converted into acetyl-CoA, mesaconate, citramalate mitochondria. administration also influenced branched-chain amino succinate levels, indicating a functional impact dehydrogenase (SDH) methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered previously unknown aspect metabolism, highlighting rapid catabolism contrasts cultured cells.
Language: Английский
Citations
1