Biology subjects

Cuenda, A.

Publications and source records attributed to Cuenda, A..

3 recordsLinked to original sources

bioRxiv2023

p38γMAPK delays myelination and remyelination and is abundant in multiple sclerosis lesions

Multiple Sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with aging, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPK{gamma} from oligodendrocyte precursors. We found that p38{gamma}MAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38{gamma}MAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38{gamma}MAPK was enriched in samples of leukocortical multiple sclerosis lesions from patients, which represent areas of failed remyelination. Our data suggest that p38{gamma} could be targeted to improve myelin repair in multiple sclerosis.

neuroscience↗

bioRxiv2022

p38γ and p38δ modulate innate immune response by regulating MEF2D activation

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.

molecular biology↗

bioRxiv2022

Evolutionary analysis of p38 stress activated kinases in unicellular relatives of animals suggests an ancestral function in osmotic stress

p38 kinases are key elements of the cellular stress response in animals. They mediate the cell response to a multitude of stress stimuli, from osmotic shock to inflammation and oncogenes. However, it is unknown how such diversity of function in stress evolved in this kinase subfamily. Here, we show that the p38 kinase was already present in a common ancestor of animals and fungi. Later, in animals, it diversified into three JNK kinases and four p38 kinases. Moreover, we identified a fifth p38 paralog in fishes and amphibians. Our analysis shows that each p38 paralog has specific amino acid substitutions around the hinge point, a region between the N-terminal and C-terminal protein domains. We showed that this region can be used to distinguish between individual paralogs and predict their specific. Finally, we showed that the response to hyperosmotic stress in Capsaspora owczarzaki, a close unicellular relative of animals, follows a typical for the p38 kinases pattern of phosphorylation-dephosphorylation. At the same time, Capsasporas cells upregulate the expression of GPD1 protein resembling an osmotic stress response in yeasts. Overall, our results show that the ancestral p38 stress pathway originated in the root of opisthokonts, most likely as a cells reaction to salinity change in the environment. In animals, the pathway became more complex and incorporated more stimuli and downstream targets due to the p38 sequence evolution in the docking and substrate binding sites around the hinge region. Overall, this study improves our understanding of the p38 evolution and opens new perspectives for the p38 research.

evolutionary biology↗