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

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 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.

p38γ and p38δ modulate innate immune response by regulating MEF2D activation

“…Since p38γ expression in p38γ/δKO cells restores TPL2 levels independently of its kinase activity ( Risco et al, 2012 ; Escós et al, 2022 ), we decided to generate a p38γ/δKIKO mouse line by crossing Mapk12 D171A/D171A and Mapk13 −/− mice. p38γ/δKIKO mice, which have catalytically inactive p38γ and lack p38δ, will not have either p38γ or p38δ kinase activity, as p38γ/δKO mice.…”

“…These results indicate that TPL2 protein levels, and therefore activation of the ERK1/2 pathway by TLR4, were regulated by p38γ independently of its kinase activity. Accordingly, we have recently demonstrated that p38γ, and also p38δ, kinase-independent activity regulates the amount of TPL2 protein at two posttranscriptional levels: (1) increasing TPL2 protein stability by binding to the complex TPL2/ABIN2/Nuclear Factor-κB1p105 (NF-κB1p105), and (2) modulating Map3k8 mRNA translation ( Escós et al, 2022 ). The RNA binding protein aconitase-1 (ACO1) interacts with the 3′ untranslated region (UTR) of Map3k8 mRNA, repressing its translation and decreasing the levels of TPL2 protein in the cells ( Escós et al, 2022 ).…”

“…The production of cytokines and chemokines triggered by C-type lectin receptor (Dectin-1) and Toll-like receptor (TLR) stimulation is reduced in macrophages lacking p38γ/p38δ ( Alsina-Beauchamp et al, 2018 ). Also, compound p38γ/p38δ deficiency substantially reduces Map3k8 mRNA translation and TPL2 protein levels in macrophages ( Alsina-Beauchamp et al, 2018 ; Risco et al, 2012 ; Escós et al, 2022 ). TPL2 is the key MAP3-kinase upstream of the MKK1–extracellular signal-regulated kinase 1/2 (ERK1/2) in myeloid cells in innate immune responses.…”

p38δ controls Mitogen- and Stress-activated Kinase-1 (MSK1) function in response to toll-like receptor activation in macrophages

“…However, the specific roles and molecular mechanisms of these kinases in the innate immune responses have not been fully characterized. Recent studies have shown that p38γ/p38δ control the levels of Tumour Progression locus 2 (TPL2), the key MAP3K upstream of ERK1/2 in myeloid cells, by regulating TPL2 mRNA translation ( Escós et al, 2022 ). This is a mechanism by which p38γ/p38δ modulate innate immune responses, since the activation of the TPL2-ERK1/2 pathway is involved in the production of several key cytokines, including Tumour Necrosis Factor α (TNFα) and Interleukin-1β (IL-1β), in response to TLR activation ( Risco et al, 2012 ).…”

p38γ and p38δ modulate innate immune response by regulating MEF2D activation

“…The production of cytokines and chemokines triggered by C-type lectin receptor (Dectin-1) and Toll like receptor (TLR) stimulation is reduced in macrophages lacking p38γ/p38δ (Alsina-Beauchamp et al ., 2018). Also, compound p38γ/p38δ deficiency substantially reduces TPL2 mRNA translation and TPL2 protein levels in macrophages (Risco et al ., 2012; Alsina-Beauchamp et al ., 2018; Escos et al ., 2022). TPL2 is the key MAP3-kinase upstream of the MKK1-ERK1/2 in myeloid cells in innate immune responses.…”