TPL2 kinase expression is regulated by the p38γ/p38δ-dependent association of aconitase-1 with TPL2 mRNA
Author
Escós López, Alejandra; Martín-Gómez, José; Gonzalez-Romero, Diego; Díaz-Mora, Ester; Francisco Velilla, María del Rosario


Entity
UAM. Departamento de Biología MolecularPublisher
National Academy of SciencesDate
2022-08-30Citation
10.1073/pnas.2204752119
Proceedings of the National Academy of Sciences (PNAS) 119.35 (2022): e2204752119
ISSN
0027-8424 (print); 1091-6490 (online)DOI
10.1073/pnas.2204752119Funded by
MCIN/AEI/10.13039/501100011033 Grants PID2019-108349RB-100 (to J.J.S.-E. and A.C.) and SAF2016-79792R (to J.J.S.-E. and A.C.)Project
Gobierno de España. PID2019-108349RB-100; Gobierno de España. SAF2016-79792REditor's Version
https://doi.org/10.1073/pnas.2204752119Subjects
Aconitate 1; Messenger RNA; Aconitate Hydratase; Phosphotransferase; Nuclear Factor Kappa B 1p10; Biología y Biomedicina / BiologíaRights
© 2022 The Author(s)
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
p38γ and p38δ (p38γ/p38δ) regulate inflammation, in part by controlling tumor progression locus 2 (TPL2) expression in myeloid cells. Here, we demonstrate that TPL2 protein levels are dramatically reduced in p38γ/p38δ-deficient (p38γ/δ2/2) cells and tissues without affecting TPL2 messenger ribonucleic acid (mRNA) expression. We show that p38γ/p38δ posttranscriptionally regulates the TPL2 amount at two different levels. p38γ/p38δ interacts with the TPL2/A20 Binding Inhibitor of NF-κB2 (ABIN2)/Nuclear Factor κB1p105 (NF-κB1p105) complex, increasing TPL2 protein stability. Additionally, p38γ/p38δ regulates TPL2 mRNA translation by modulating the repressor function of TPL2 30 Untranslated region (UTR) mediated by its association with aconitase-1 (ACO1). ACO1 overexpression in wild-type cells increases the translational repression induced by TPL2 30UTR and severely decreases TPL2 protein levels. p38δ binds to ACO1, and p38δ expression in p38γ/δ2/2 cells fully restores TPL2 protein to wild-type levels by reducing the translational repression of TPL2 mRNA. This study reveals a unique mechanism of posttranscriptional regulation of TPL2 expression, which given its central role in innate immune response, likely has great relevance in physiopathology
Files in this item
Google Scholar:Escós López, Alejandra
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Martín-Gómez, José
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Gonzalez-Romero, Diego
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Díaz-Mora, Ester
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Francisco Velilla, María del Rosario
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Santiago, César
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Cuezva Marcos, José Manuel
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Domínguez Zorita, Sonia
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Martínez-Salas, Encarnación
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Sonenberg, Nahum
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Sanz Ezquerro, Juan José
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Jafarnejad, Seyed Mehdi
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Cuenda Mendez, Ana
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