Although the physiological roles of p38γ and p38δ signalling pathways are largely unknown, new genetic and pharmacological tools are providing groundbreaking information on the function of these two ...stress-activated protein kinases. Recent studies show the importance of p38γ and p38δ in the regulation of processes as diverse as cytokine production, protein synthesis, exocytosis, cell migration, gene expression, and neuron activity, which have an acute impact on the development of pathologies related to inflammation, diabetes, neurodegeneration, and cancer. These recent breakthroughs are resolving some of the questions that have long been asked regarding the function of p38γ and p38δ in biology and pathology.
The roles of the alternative p38 mitogen-activated protein kinases (MAPKs) p38γ and p38δ have been disregarded in many studies and remain largely unknown.
The identification of novel p38γ and p38δ substrates ascribes new biological functions to these kinases.
The finding that p38γ and p38δ modulate the inflammatory/immune response is a major breakthrough in signalling research and positions these kinases as potential therapeutic targets.
Overall and tissue-specific p38γ and p38δ that these kinases also have a relevant role in the regulation of tumour development, cardiac hypertrophy, and glucose homeostasis.
p38 Signalling Pathway Sanz-Ezquerro, Juan José; Cuenda, Ana
International journal of molecular sciences,
01/2021, Volume:
22, Issue:
3
Journal Article
Peer reviewed
Open access
p38 Mitogen activated protein kinases (p38MAPK) are a highly evolutionary conserved group of protein kinases, which are central for cell adaptation to environmental changes as well as for immune ...response, inflammation, tissue regeneration, and tumour formation ....
Normal organogenesis cannot be recapitulated in vitro for mammalian organs, unlike in species including Drosophila and zebrafish. Available 3D data in the form of ex vivo images only provide discrete ...snapshots of the development of an organ morphology. Here, we propose a computer-based approach to recreate its continuous evolution in time and space from a set of 3D volumetric images. Our method is based on the remapping of shape data into the space of the coefficients of a spherical harmonics expansion where a smooth interpolation over time is simpler. We tested our approach on mouse limb buds and embryonic hearts. A key advantage of this method is that the resulting 4D trajectory can take advantage of all the available data while also being able to interpolate well through time intervals for which there are little or no data. This allows for a quantitative, data-driven 4D description of mouse limb morphogenesis.
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•Computer-based method recreating a 3D plus time evolution of a set of volumetric images•Technique based on the interpolation of the coefficients of spherical harmonics•Data-driven quantitative 4D description of limb and heart morphogenesis•Quantitatively reliable baseline description of organ development
Continuous time-lapse imaging of developing mammalian organs is not yet possible. Dalmasso et al. propose a computer-based approach to recreate a continuous evolution in time and space from a set of 3D volumetric images using spherical harmonics. The result allows for a data-driven quantitative 4D description of limb and heart morphogenesis.
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.
Candida albicans is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency ...and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to C. albicans. We describe a new TAK1‐TPL2‐MKK1‐ERK1/2 pathway in macrophages, which is activated by Dectin‐1 engagement and positively regulated by p38γ/p38δ. In mice, p38γ/p38δ deficiency protects against C. albicans infection by increasing ROS and iNOS production and thus the antifungal capacity of neutrophils and macrophages, and by decreasing the hyper‐inflammation that leads to severe host damage. Leucocyte recruitment to infected kidneys and production of inflammatory mediators are decreased in p38γ/δ‐null mice, reducing septic shock. p38γ/p38δ in myeloid cells are critical for this effect. Moreover, pharmacological inhibition of p38γ/p38δ in mice reduces fungal burden, revealing that these p38MAPKs may be therapeutic targets for treating C. albicans infection in humans.
Synopsis
Candida albicans infections cause high mortality in immunocompromised patients. This study shows that p38γ/p38δ are essential for the immune response to C. albicans by regulating host antifungal activity. p38γ/p38δ inhibition reduces mice fungal burden, establishing p38γ/p38δ as therapeutic targets.
Deletion of p38γ/p38δ protects mice from C. albicans infection.
p38γ/p38δ control fungicidal capacity through ROS and iNOS production.
p38γ/p38δ regulate the inflammatory response to C. albicans through a new Dectin‐1 pathway in macrophages.
Chemical inhibition of p38γ/p38δ reduces fungal burden in a candidiasis mouse model.
Candida albicans infections cause high mortality in immunocompromised patients. This study shows that p38γ/p38δ are essential for the immune response to C. albicans by regulating host antifungal activity. p38γ/p38δ inhibition reduces mice fungal burden, establishing p38γ/p38δ as therapeutic targets.
An often overlooked aspect of digit development is the special nature of the terminal phalanx, a specialized structure with characteristics distinct from other phalanges, for example the presence of ...ectodermal derivatives such as nails and claws. Here, we describe the unique ossification pattern of distal phalanges and characteristic gene expression in the digit tips of chick and duck embryos. Our results show that the distal phalanx of chick wing digit 1 is a genuine tip with a characteristic ossification pattern and expression of Bambi and Sp8; however, the terminal phalanx of digits 2* and 3 is not a genuine tip, and these are therefore truncated digits. Bambi and Sp8 expression in the chick wing provides a direct molecular assessment of digit identity changes after experimental manipulations of digit primordia. In contrast, digits 1 and 2 of the duck wing both possess true tips. Although chick wing-tip development was not rescued by application of Fgf8, this treatment induced the development of extra phalanges. Grafting experiments show that competence for tip formation, including nails, is latent in the interdigital tissue. Our results deepen understanding of the mechanisms of digit tip formation, highlighting its developmental autonomy and modular nature, with implications for digit reduction or loss during evolution. * Numbering of wing digits is 1, 2, 3 from anterior to posterior.
Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using
deficient (p38γ/δKO) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in ...myeloid cells. This could obscure p38γ/p38δ roles, since TPL2 is essential for regulating inflammation. Here we generated a
/
(p38γ/δKIKO) mouse, expressing kinase-inactive p38γ and lacking p38δ. This mouse exhibited normal TPL2 levels, making it an excellent tool to elucidate specific p38γ/p38δ functions. p38γ/δKIKO mice showed a reduced inflammatory response and less susceptibility to LPS-induced septic shock and
infection than wild-type mice. Gene expression analyses in LPS-activated WT and p38γ/δKIKO macrophages revealed that p38γ/p38δ regulated numerous genes implicated in innate immune response. Additionally, phospho-proteomic analyses and
kinase assays showed that the transcription factor myocyte enhancer factor-2D (MEF2D) was phosphorylated at Ser444 via p38γ/p38δ. Mutation of MEF2D Ser444 to the non-phosphorylatable residue Ala increased its transcriptional activity and the expression of
and
mRNA. These results suggest that p38γ/p38δ govern innate immune responses by regulating MEF2D phosphorylation and transcriptional activity.
Arid3b, a member of the conserved ARID family of transcription factors, is essential for mouse embryonic development but its precise roles are poorly understood. Here, we show that Arid3b is ...expressed in the myocardium of the tubular heart and in second heart field progenitors. Arid3b-deficient embryos show cardiac abnormalities, including a notable shortening of the poles, absence of myocardial differentiation and altered patterning of the atrioventricular canal, which also lacks epithelial-to-mesenchymal transition. Proliferation and death of progenitors as well as early patterning of the heart appear normal. However, DiI labelling of second heart field progenitors revealed a defect in the addition of cells to the heart. RNA microarray analysis uncovered a set of differentially expressed genes in Arid3b-deficient tissues, including Bhlhb2, a regulator of cardiomyocyte differentiation, and Lims2, a gene involved in cell migration. Arid3b is thus required for heart development by regulating the motility and differentiation of heart progenitors. These findings identify Arid3b as a candidate gene involved in the aetiology of human congenital malformations.
Abbreviations AOM azoxymethane CAC colitis-associated colorectal cancer CD Crohn's disease CRC colorectal cancer DSS dextran sodium sulfate IBD inflammatory bowel disease MAPK mitogen-activated ...protein kinase miR microRNAs p38γ/p38δ p38γ and p38δ UC ulcerative colitis WT Wild type Dear Editor, Colorectal cancer (CRC) is the second leading cause of cancer death according to the World Health Organization. Patients with inflammatory bowel disease (IBD), ulcerative colitis (UC) or Crohn's disease (CD) are at increased risk of developing colitis-associated CRC (CAC) 1; however, our understanding of the inflammation-cancer interplay at the molecular level is still limited. p38 mitogen-activated protein kinases (MAPKs) (p38α, p38β, p38γ and p38δ) modulate the inflammatory response which contribute to CAC development 2. p38α (called p38) has been a therapeutic target in CD treatment, but these treatments have not progressed beyond phase I/II clinical trials 2. Interestingly, the less studied p38γ and p38δ (p38γ/p38δ) are essential in the immune response and regulate inflammatory molecule production 2–6. ...the importance of p38γ/p38δ in CRC development has been established in vitro and in an azoxymethane-dextran sodium sulfate (AOM-DSS)-induced CAC model using p38γ/p38δ-knockout mice 2, 5. Crohn's disease; CRC: colorectal cancer; DSS: dextran sodium sulfate; FPKM: fragments per kilobase of transcript per million mapped reads; ELISA: enzyme-linked immunosorbent assay; GEO: gene expression omnibus; GO: gene ontology; IBD: inflammatory bowel disease; MAPK: mitogen-activated protein kinase; miRNA: microRNAs; p38γ/p38δ: p38γ and p38δ; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SEM: standard error of the mean; TCGA:
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