TPL2 kinase expression is regulated by the p38γ/p38δ-dependent association of aconitase-1 with TPL2 mRNA

Alejandra Escós, José Martín-Gómez, Diego González-Romero, Ester Díaz-Mora, Rosario Francisco-Velilla, Cesar Santiago, José M Cuezva, Sonia Domínguez-Zorita, Encarnación Martínez-Salas, Nahum Sonenberg, Juan José Sanz-Ezquerro, Seyed Mehdi Jafarnejad, Ana Cuenda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Downloads (Pure)


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/δ-/-) 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 3' Untranslated region (UTR) mediated by its association with aconitase-1 (ACO1). ACO1 overexpression in wild-type cells increases the translational repression induced by TPL2 3'UTR and severely decreases TPL2 protein levels. p38δ binds to ACO1, and p38δ expression in p38γ/δ-/- 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.

Original languageEnglish
Article numbere2204752119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
Publication statusPublished - 22 Aug 2022


Dive into the research topics of 'TPL2 kinase expression is regulated by the p38γ/p38δ-dependent association of aconitase-1 with TPL2 mRNA'. Together they form a unique fingerprint.

Cite this