TPL2 Kinase Expression is Regulated by the P38γ/p38δ-dependent Association of Aconitase-1 with MRNA

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2022 Aug 22

PMID 35994673

Authors

Alejandra Escos

Jose Martin-Gomez

Diego Gonzalez-Romero

Ester Diaz-Mora

Rosario Francisco-Velilla

Cesar Santiago

Jose M Cuezva

Sonia Dominguez-Zorita

Encarnacion Martinez-Salas

Nahum Sonenberg

Juan Jose Sanz-Ezquerro

Seyed Mehdi Jafarnejad

Ana Cuenda

Affiliations

Soon will be listed here.

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/δ) cells and tissues without affecting 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 mRNA translation by modulating the repressor function of 3' Untranslated region (UTR) mediated by its association with aconitase-1 (ACO1). ACO1 overexpression in wild-type cells increases the translational repression induced by 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 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.

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