Nitro-oleic acid regulates T cell activation through post-translational modification of calcineurin
Entity
UAM. Departamento de Biología MolecularPublisher
National Academy of SciencesDate
2023-01-18Citation
10.1073/pnas.2208924120
Proceedings of the National Academy of Sciences of the United States of America 120.4 (2023): e208924120
ISSN
0027-8424 (print); 1091-6490 (online)DOI
10.1073/pnas.2208924120Project
Gobierno de España. RTI2018-100815-B-I00; Gobierno de España. PID2021-122348NB-I00Editor's Version
https://doi.org/10.1073/pnas.2208924120Subjects
NFAT; Calcineurin; Inflammation; Nitro-Fatty Acids; T Cells; Biología y Biomedicina / BiologíaRights
© 2023 the Author(s). Published by PNAS.Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Nitro-fatty acids (NO2-FAs) are unsaturated fatty acid nitration products that exhibit anti-inflammatory actions in experimental mouse models of autoimmune and allergic diseases. These electrophilic molecules interfere with intracellular signaling pathways by reversible post-translational modification of nucleophilic amino-acid residues. Several regulatory proteins have been identified as targets of NO2-FAs, modifying their activity and promoting gene expression changes that result in anti-inflammatory effects. Herein, we report the effects of nitro-oleic acid (NO2-OA) on pro-inflammatory T cell functions, showing that 9- and 10-NOA, but not their oleic acid precursor, decrease T cell proliferation, expression of activation markers CD25 and CD71 on the plasma membrane, and IL-2, IL-4, and IFN-γ cytokine gene expressions. Moreover, we have found that NO2-OA inhibits the transcriptional activity of nuclear factor of activated T cells (NFAT) and that this inhibition takes place through the regulation of the phosphatase activity of calcineurin (CaN), hindering NFAT dephosphorylation, and nuclear translocation in activated T cells. Finally, using mass spectrometry-based approaches, we have found that NO2-OA nitroalkylates CaNA on four Cys (Cys129, 228, 266, and 372), of which only nitroalkylation on Cys372 was of importance for the regulation of CaN phosphatase activity in cells, disturbing functional CaNA/CaNB heterodimer formation. These results provide evidence for an additional mechanism by which NO2-FAs exert their anti-inflammatory actions, pointing to their potential as therapeutic bioactive lipids for the modulation of harmful T cell-mediated immune responses
Files in this item
Google Scholar:Bago, Ángel
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Cayuela, M. Laura
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Gil, Alba
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Calvo, Enrique
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Vázquez, Jesús
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Queiro, Antonio
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Schopfer, Francisco J.
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Radi, Rafael
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Serrador, Juan M.
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Íñiguez Peña, Miguel Ángel
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