P38 MAPK-dependent phosphorylation of TFEB promotes monocyte-to-macrophage differentiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE217608 | GEO | 2022/12/06
REPOSITORIES: GEO
Similar Datasets
Project description:In addition to the role in lysosomal biogenesis and autophagy, TFEB has been described to participate in the control of inflammation and host defense against pathogen infection The activation of TFEB in toll-like receptor-induced or bacteria exposed macrophages is regulated by a mechanism independent of mTORC1 inactivation, suggesting that other protein kinases may participate in the regulation of TFEB function during macrophage activation In this study, we identified a novel role of p38 MAPK in TFEB regulation. We showed p38-dependent TFEB phosphorylation at serine 401 (S401) in response to a variety of stress conditions, including oxidative stress, UVC irradiation, growth factors, and lipopolysaccharide (LPS) treatment. Furthermore, inhibition of S401 phosphorylation during PMA-induced monocyte differentiation prevented TFEB nuclear accumulation and resulted in reduced expression of multiple immune genes. TFEB-S401A expressing M0 macrophages also failed to efficiently polarize into M1 inflammatory macrophages, showing defective upregulation of cytokines and chemokines, as well as reduced inflammasome activation. We conclude that TFEB is a target of the p38 signaling pathway that is required for monocyte/macrophage differentiation and function.
2022-12-06 | GSE201826 | GEO
Project description:p38 MAPK-dependent phosphorylation of TFEB promotes monocyte-to-macrophage differentiation
| PRJNA833123 | ENA
Project description:p38 MAPK-dependent phosphorylation of TFEB promotes monocyte-to-macrophage differentiation
| PRJNA899824 | ENA
Project description:The mitogen-activated protein kinase (MAPK) p38 pathway is reported to regulate macrophage responses to lipopolysaccharide (LPS) at least partly via the phosphorylation of the mRNA-destabilizing factor tristetraprolin (TTP). LPS-activated MAPK p38 phosphorylates and activates the downstream kinase MAPK-activated protein kinase 2 (MK2), which then phosphorylates serines 52 and 178 of TTP, resulting in loss of mRNA-destabilizing activity. As a consequence, mRNAs that contain binding sites for TTP are stabilized in a manner that is acutely sensitive to the activity of the MAPK p38 pathway. Dual specificity phosphatase 1 (DUSP1) dephosphorylates and inactivates MAPK p38. Dusp1-/- macrophages overexpress a number of pro-inflammatory mediators, but their genome-wide responses to LPS have not yet been described in detail. Dusp1-/- mice are exceptionally sensitive to a wide variety of inflammatory challenges, including experimental models of endotoxemia or sepsis. It has been suggested (but not yet proven) that DUSP1 controls the inflammatory response of macrophages in part via the regulation of MAPK p38 activity and TTP phosphorylation status. We generated a mouse knock-in strain, in which codons 52 and 178 of the endogenous Zfp36 gene (which encodes TTP) were mutated to alanine codons. The mutation gives rise to a constitutively active form of TTP, which cannot be inactivated via the p38 MAPK pathway. The Zfp36aa/aa strain was back-crossed against C57/BL6 for > 10 generations. We also generated a double-targeted strain in which the Zfp36 mutation was combined with disruption of the Dusp1 gene. This expression array describes LPS responses of primary mouse bone marrow-derived macrophages of four genotypes, and closely matched genetic background: wild type (Dusp1+/+ : Zfp36+/+); TTP mutant (Zfp36aa/aa); DUSP1 knock out (Dusp1-/-); and double targeted (Dusp1-/- : Zfp36aa/aa). The data provide a comprehensive picture of the impact of Dusp1 deletion or TTP mutation on the responses of primary macrophages to LPS. They also demonstrate that the excessive inflammatory responses of Dusp1-/- macrophages are largely a consequence of the phosphorylation and inactivation of TTP. Genome wide expression profiles of wild type, Dusp1-/-, Zfp36aa/aa and Dusp1-/-/Zfp36aa/aa M-CSF derived macrophages, stimulated with LPS for 1 or 4 hours
2015-05-15 | E-GEOD-68449 | biostudies-arrayexpress
Project description:In response to environmental stressors and a variety of inflammatory cytokines, p38 MAPKs become directly activated. Here we report the human glucocorticoid receptor (GR) Serine 134 as a novel target for p38 MAPK. Unlike most other phosphorylation events that occur on the GR, phosphorylation of Ser134 was found to be hormone-independent in several human and rat cell types. Instead we found phosphorylation of Ser134 was induced by a variety of stress-activating stimuli, including: glucose starvation, ultraviolet irradiation, osmotic shock, and oxidative stress. Pharmacological inhibitors and shRNA-mediated knockdown experiments correlate this phosphorylation with the activation of p38 MAPK. Compared to wild-type GR, cells expressing a mutant receptor incapable of phosphorylation at Ser134 (S134A GR) had a significantly altered hormone-dependent genome-wide transcriptional response to glucocorticoids. Moreover, we show that although WT GR regulated roughly half as many genes as S134A GR, WT receptor selectively activated significantly more genes associated with endocrine and inflammatory disease than the mutant receptor, suggesting that the phosphorylation status of Ser134 is critical for modulating GR function. Phosphorylation of Ser134 did not alter either nuclear translocation or the stability of the GR protein in the absence or presence of ligand. However, phosphorylation of Ser134 significantly increased the association of the GR with the zeta isoform the 14-3-3 class of signaling proteins, resulting in a blunted hormone-dependent transcriptional response of LAD1 and IGFBP1 but not GILZ. Together these data suggest that the phosphorylation of Ser134 acts as a molecular sensor on the GR, monitoring the level of cellular stress to allow for altered 14-3-3zeta cofactor association, ultimately modifying glucocorticoid signaling in a gene-dependent manner. Our results reveal one mechanism that may allow cellular stress to dictate the transcriptional response of cells to hormone. U2OS cells, a human osteosarcoma cell line, were transfected with either WT GR or S134A GR and put under antibiotic selection to produce a stable mixed population of cells expressing comparable levels of GR. 10^6 cells were treated with 100nM Dexamethasone (DEX) or vehicle control for 6 hours. Three biological and one hybridization replicate are included for each sample.
2011-10-04 | E-GEOD-28912 | biostudies-arrayexpress
Project description:The mitogen-activated protein kinase (MAPK) p38 pathway is reported to regulate macrophage responses to lipopolysaccharide (LPS) at least partly via the phosphorylation of the mRNA-destabilizing factor tristetraprolin (TTP). LPS-activated MAPK p38 phosphorylates and activates the downstream kinase MAPK-activated protein kinase 2 (MK2), which then phosphorylates serines 52 and 178 of TTP, resulting in loss of mRNA-destabilizing activity. As a consequence, mRNAs that contain binding sites for TTP are stabilized in a manner that is acutely sensitive to the activity of the MAPK p38 pathway. Dual specificity phosphatase 1 (DUSP1) dephosphorylates and inactivates MAPK p38. Dusp1-/- macrophages overexpress a number of pro-inflammatory mediators, but their genome-wide responses to LPS have not yet been described in detail. Dusp1-/- mice are exceptionally sensitive to a wide variety of inflammatory challenges, including experimental models of endotoxemia or sepsis. It has been suggested (but not yet proven) that DUSP1 controls the inflammatory response of macrophages in part via the regulation of MAPK p38 activity and TTP phosphorylation status. We generated a mouse knock-in strain, in which codons 52 and 178 of the endogenous Zfp36 gene (which encodes TTP) were mutated to alanine codons. The mutation gives rise to a constitutively active form of TTP, which cannot be inactivated via the p38 MAPK pathway. The Zfp36aa/aa strain was back-crossed against C57/BL6 for > 10 generations. We also generated a double-targeted strain in which the Zfp36 mutation was combined with disruption of the Dusp1 gene. This expression array describes LPS responses of primary mouse bone marrow-derived macrophages of four genotypes, and closely matched genetic background: wild type (Dusp1+/+ : Zfp36+/+); TTP mutant (Zfp36aa/aa); DUSP1 knock out (Dusp1-/-); and double targeted (Dusp1-/- : Zfp36aa/aa). The data provide a comprehensive picture of the impact of Dusp1 deletion or TTP mutation on the responses of primary macrophages to LPS. They also demonstrate that the excessive inflammatory responses of Dusp1-/- macrophages are largely a consequence of the phosphorylation and inactivation of TTP.
2015-05-15 | GSE68449 | GEO
Project description:Major- and minor-group rhinoviruses enter their host by binding to the cell surface molecules ICAM-1 and LDL-R, respectively, which are present on both macrophages and epithelial cells. Although epithelial cells are the primary site of productive HRV infection, previous studies have implicated macrophages in establishing the cytokine dysregulation that occurs during rhinovirus-induced asthma exacerbations. Even though major- and minor-group rhinoviruses are nearly genetically identical, these viruses do not replicate with equal success in monocyte-lineage cell lines. In human primary macrophages, differential mitochondrial activity and signaling pathway activation was observed between major- and minor-group rhinovirus upon initial HRV binding, indicating discordant receptor-dependent response to these rhinovirus types. As well, variances in phosphorylation of kinases (p38, JNK, ERK5) and transcription factors (ATF-2, CREB, CEBP-alpha) were observed between the major- and minor- group HRV treatments. The difference between major- and minor- group HRV activation of signaling pathways was confirmed through RNA-sequencing and observation of differential production of the asthma-relevant cytokines CCL20, CCL2, and IL-10. This is the first report of genetically similar viruses eliciting dissimilar cytokine release, transcription factor phosphorylation, and MAPK activation from macrophages. These results suggest that receptor dependence plays a role in establishing the inflammatory microenvironment initiated in part by monocytic-lineage cells in the human airway upon exposure to rhinovirus. RNA sequencing of monocyte-derived macrophages after mock infection or infection by HRV16 or HRV1A
2014-03-14 | E-GEOD-55271 | biostudies-arrayexpress
Project description:In response to environmental stressors and a variety of inflammatory cytokines, p38 MAPKs become directly activated. Here we report the human glucocorticoid receptor (GR) Serine 134 as a novel target for p38 MAPK. Unlike most other phosphorylation events that occur on the GR, phosphorylation of Ser134 was found to be hormone-independent in several human and rat cell types. Instead we found phosphorylation of Ser134 was induced by a variety of stress-activating stimuli, including: glucose starvation, ultraviolet irradiation, osmotic shock, and oxidative stress. Pharmacological inhibitors and shRNA-mediated knockdown experiments correlate this phosphorylation with the activation of p38 MAPK. Compared to wild-type GR, cells expressing a mutant receptor incapable of phosphorylation at Ser134 (S134A GR) had a significantly altered hormone-dependent genome-wide transcriptional response to glucocorticoids. Moreover, we show that although WT GR regulated roughly half as many genes as S134A GR, WT receptor selectively activated significantly more genes associated with endocrine and inflammatory disease than the mutant receptor, suggesting that the phosphorylation status of Ser134 is critical for modulating GR function. Phosphorylation of Ser134 did not alter either nuclear translocation or the stability of the GR protein in the absence or presence of ligand. However, phosphorylation of Ser134 significantly increased the association of the GR with the zeta isoform the 14-3-3 class of signaling proteins, resulting in a blunted hormone-dependent transcriptional response of LAD1 and IGFBP1 but not GILZ. Together these data suggest that the phosphorylation of Ser134 acts as a molecular sensor on the GR, monitoring the level of cellular stress to allow for altered 14-3-3zeta cofactor association, ultimately modifying glucocorticoid signaling in a gene-dependent manner. Our results reveal one mechanism that may allow cellular stress to dictate the transcriptional response of cells to hormone.
2011-10-05 | GSE28912 | GEO
Project description:HAMLET triggers a p38- and ER stress-dependent death response in carcinoma cells. Transcriptome and proteome analysis detected an increase in p38 expression and phosphorylation exclusively in carcinoma cells and p38 inhibitors delayed the death response to HAMLET in carcinoma and lymphoma cells. ER stress gene expression was also increased in tumor cells and HAMLET triggered rapid XBP1 mRNA splicing, eIF2a phosphorylation, and ATF6 cleavage as well as Hsc70 and CHOP activation, suggesting that ER stress caused by HAMLET may trigger p38 phosphorylation and death. The p38 inhibitor reduced the transcription of both p38 and ER stress gene transcription. Healthy differentiated cells, in contrast, showed no alteration in p38 signaling but a rapid innate immune response was detected and the cells survived HAMLET challenge. 2 cell lines, time course, HAMLET treatment
2010-08-24 | E-GEOD-23772 | biostudies-arrayexpress
Project description:Maintenance of lysosomal integrity is essential for cell viability. Upon injury, lysosomes may be targeted for degradation via a form of selective autophagy known as lysophagy, in which autophagosomes engulf damaged lysosomes following the recruitment of adaptor proteins. One of these adaptors, SQSTM1/p62, promotes lysophagy via liquid-like phase separation on damaged lysosomes. The formation of p62 condensates is regulated by the heat shock protein HSP27. Here, we demonstrate a direct interaction between HSP27 and p62. We used structural modeling to predict the binding interface between HSP27 and p62, and found several disease-associated mutations that map to this interface and disrupt the interaction. We then used proteomics to identify post-translational modifications of HSP27 that determine HSP27 recruitment to stressed lysosomes, finding robust phosphorylation at Serine residues 15, 78, and 82. We characterized the signaling mechanism leading to HSP27 phosphorylation. We find that p38 MAPK and its effector kinase MK2 are activated upon lysosomal damage by the kinase mTOR and the production of intracellular reactive oxygen species (ROS). Increased ROS activates p38 MAPK, which in turn allows MK2-dependent phosphorylation of HSP27. Either depletion of HSP27 or inhibition of HSP27 phosphorylation alters the liquidity of p62 condensates, significantly inhibiting p62-dependent lysophagy. Thus, we define a novel lysosomal quality control mechanism in which lysosomal injury triggers a p38 MAPK/MK2 signaling cascade regulating p62-dependent lysophagy. Further, this signaling cascade is activated by a variety of cellular stressors, including oxidative and heat stress, suggesting that other forms of selective autophagy may be regulated by p38 MAPK/MK2/HSP27.
2024-10-22 | PXD051927 | Pride