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bioRxiv · 10.1101/2022.12.09.519777

p38γ and p38δ modulate innate immune response by regulating MEF2D activation

Cuenda, A.·Escos, A.·Diaz-Mora, E.·Fajardo, P.·Gonzalez-Romero, D.·Risco, A.·Martin-Gomez, J.·Bonneil, E.·Sonenberg, N.·Jafarnejad, S. M.·Pattison, M.·Sanz-Ezquerro, J. J.·Ley, S. C.
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Abstract

Evidence implicating p38{gamma} and p38{delta} (p38{gamma}/p38{delta}) in inflammation are mainly based on experiments using p38{gamma}/p38{delta} deficient (p38{gamma}/{delta}-/-) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38{gamma}/p38{delta} roles, since TPL2 is essential for regulating inflammation. Here we generated a p38{gamma}D171A/D171A/p38{delta}-/- (p38{gamma}/{delta}KIKO) mouse, expressing kinase-inactive p38{gamma} and lacking p38{delta}. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38{gamma}/p38{delta} functions. p38{gamma}/{delta}KIKO mice showed a reduced inflammatory response and less susceptibility to LPS-induced septic shock and Candida albicans infection than wild-type mice. Gene expression analyses in LPS-activated WT and p38{gamma}/{delta}KIKO macrophages revealed that p38{gamma}/p38{delta} regulated numerous genes implicated in innate immune response. Additionally, phospho-proteomic analyses and in vitro kinase assays showed that the transcription factor myocyte enhancer factor-2D (MEF2D) was phosphorylated at Ser444 via p38{gamma}/p38{delta}. Mutation of MEF2D Ser444 to the non-phosphorylatable residue Ala increased its transcriptional activity and the expression of iNOS and IL-1{beta} mRNA. These results suggest that p38{gamma}/p38{delta} govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity.

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Cuenda, A., Escos, A., Diaz-Mora, E., Fajardo, P., Gonzalez-Romero, D., Risco, A., Martin-Gomez, J., Bonneil, E., Sonenberg, N., Jafarnejad, S. M., Pattison, M., Sanz-Ezquerro, J. J., Ley, S. C.. 2022-12-09. p38γ and p38δ modulate innate immune response by regulating MEF2D activation. https://doi.org/10.1101/2022.12.09.519777

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