TPL2 kinase expression is regulated by the p38 gamma/p38 delta-dependent association of aconitase-1 with TPL2 mRNA

p38 gamma and p38 delta (p38 gamma/p38 delta) 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 p38 gamma/p38 delta-deficient (p38 gamma/(delta-/-)) cells and tissues without affecting TPL2 messenger ribonucleic acid (mRNA) expression. We show that p38 gamma/p38 delta posttranscriptionally regulates the TPL2 amount at two different levels. p38 gamma/p38 delta interacts with the TPL2/A20 Binding Inhibitor of NF-kappa B2 (ABIN2)/Nuclear Factor kappa B1p105 (NF-kappa B1p105) complex, increasing TPL2 protein stability. Additionally, p38 gamma/p38 delta 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. p38 delta binds to ACO1, and p38 delta expression in p38 gamma/d2/2 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.