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Regulation of the Golgi Apparatus by p38 and JNK Kinases during Cellular Stress Responses.

ABSTRACT: p38 and c-Jun N-terninal kinase (JNK) are activated in response to acute stress and inflammatory signals. Through modification of a plethora of substrates, these kinases profoundly re-shape cellular physiology for the optimal response to a harmful environment and/or an inflammatory state. Here, we utilized phospho-proteomics to identify several hundred substrates for both kinases. Our results indicate that the scale of signaling from p38 and JNK are of a similar magnitude. Among the many new targets, we highlight the regulation of the transcriptional regulators grb10-interacting GYF protein 1 and 2 (GIGYF1/2) by p38-dependent MAP kinase-activated protein kinase 2 (MK2) phosphorylation and 14-3-3 binding. We also show that the Golgi apparatus contains numerous substrates, and is a major target for regulation by p38 and JNK. When activated, these kinases mediate structural rearrangement of the Golgi apparatus, which positively affects protein flux through the secretory system. Our work expands on our knowledge about p38 and JNK signaling with important biological ramifications.

SUBMITTER: Nordgaard C

PROVIDER: S-EPMC8431686 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Regulation of the Golgi apparatus by p38 and JNK kinases during cellular stress responses

Project description:p38 and JNK are activated in response to acute stress and inflammatory signals. Through modification of a plethora of substrates, these kinases profoundly re-shape cellular physiology for the optimal response to a harmful environment and/or an inflammatory state. Here, we utilized phospho-proteomics to identify several hundred substrates for both kinases. Our results indicate that the scale of signaling from p38 and JNK are of a similar magnitude. Among the many new targets, we highlight the regulation of the transcriptional regulators GIGYF1 and 2 by p38-dependent MK2 phosphorylation and 14-3-3 binding. We also show that the Golgi apparatus contains numerous substrates, and is a major target for regulation by p38 and JNK. When activated, these kinases mediate structural rearrangement of the Golgi apparatus which positively affects protein flux through the secretory system. Our work expands on our knowledge about p38 and JNK signaling with important biological ramifications.

2021-09-13 | PXD028151 | Pride

beta3-adrenergic receptor induction of adipocyte inflammation requires lipolytic activation of stress kinases p38 and JNK.

Project description:Activation of beta-adrenergic receptors (AR) in adipocytes triggers acute changes in metabolism that can alter patterns of gene expression. This work examined the mechanisms by which activation of hormone sensitive lipase (HSL) induces expression of inflammatory cytokines in adipocytes in vivo and model adipocytes in vitro. beta3-AR activation in mice triggered expression of inflammatory genes CCL2, IL-6, and PAI-1, as well as endoplasmic reticulum (ER) stress markers GRP78 and CHOP. Pharmacological inhibition of HSL blocked induction of inflammatory genes, but not ER stress markers. Promoting intracellular accumulation of free fatty acids (FFAs) in 3T3-L1 adipocytes increased expression of inflammatory cytokines, whereas inhibiting ceramide synthesis partly blocked PAI-1 expression, but not IL-6. Induction of inflammatory markers in vivo and in vitro was preceded by phosphorylation of p38 and JNK, and inhibition of HSL prevented activation of these kinases. Experiments with pharmacological inhibitors of specific MAP kinases demonstrated the importance of p38 MAPK as a mediator of lipolysis-induced inflammation in vivo and in vitro. Together, these results demonstrate that FFAs liberated by HSL activate p38 and JNK, and p38 mediates pro-inflammatory cytokine expression in adipose tissue.

| S-EPMC2906652 | biostudies-literature

DUX4 expression activates JNK and p38 MAP kinases in myoblasts

Project description:Facioscapulohumoral muscular dystrophy (FSHD) is a progressive muscle wasting disease caused by misexpression of the DUX4 transcription factor. DUX4 expression in skeletal muscle cells results in a dramatic alteration in their transcriptional profile and cellular phenotype and subsequently, cell death. To gain insight into the kinetics of DUX4-induced stresses, we activated DUX4 expression in myoblasts and performed longitudinal RNA sequencing paired with proteomics and phosphoproteomics. This analysis revealed changes in cellular physiology such as DNA damage and altered mRNA splicing before detectable changes in protein levels. Implementation of phosphoproteomics uncovered that widespread changes in protein phosphorylation preceded changes in protein levels indicating that alterations in kinase signaling may play a role in DUX4-mediated stress and cell death. Here we demonstrate that two stress-responsive MAP kinase pathways, JNK and p38, are activated in response to DUX4 expression. Pharmacological inhibition of either of these pathways ameliorated DUX4-mediated cell death in myoblasts. These findings uncover JNK as a novel pathway involved in DUX4-mediated cell death, as well as provide additional insights into the role of the p38 pathway, a clinical target for the treatment of FSHD.

2022-10-09 | GSE205421 | GEO

DUX4 expression activates JNK and p38 MAP kinases in myoblasts.

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is caused by misexpression of the DUX4 transcription factor in skeletal muscle that results in transcriptional alterations, abnormal phenotypes and cell death. To gain insight into the kinetics of DUX4-induced stresses, we activated DUX4 expression in myoblasts and performed longitudinal RNA sequencing paired with proteomics and phosphoproteomics. This analysis revealed changes in cellular physiology upon DUX4 activation, including DNA damage and altered mRNA splicing. Phosphoproteomic analysis uncovered rapid widespread changes in protein phosphorylation following DUX4 induction, indicating that alterations in kinase signaling might play a role in DUX4-mediated stress and cell death. Indeed, we demonstrate that two stress-responsive MAP kinase pathways, JNK and p38, are activated in response to DUX4 expression. Inhibition of each of these pathways ameliorated DUX4-mediated cell death in myoblasts. These findings uncover that the JNK pathway is involved in DUX4-mediated cell death and provide additional insights into the role of the p38 pathway, a clinical target for the treatment of FSHD.

| S-EPMC10655719 | biostudies-literature

Growth of the Mammalian Golgi Apparatus during Interphase.

Project description:During the cell cycle, genetic materials and organelles are duplicated to ensure that there is sufficient cellular content for daughter cells. While Golgi growth in interphase has been observed in lower eukaryotes, the elaborate ribbon structure of the mammalian Golgi apparatus has made it challenging to monitor. Here we demonstrate the growth of the mammalian Golgi apparatus in its protein content and volume during interphase. Through ultrastructural analyses, physical growth of the Golgi apparatus was revealed to occur by cisternal elongation of the individual Golgi stacks. By examining the timing and regulation of Golgi growth, we established that Golgi growth starts after passage through the cell growth checkpoint at late G1 phase and continues in a manner highly correlated with cell size growth. Finally, by identifying S6 kinase 1 as a major player in Golgi growth, we revealed the coordination between cell size and Golgi growth via activation of the protein synthesis machinery in early interphase.

| S-EPMC5007790 | biostudies-literature

Aging-associated increase in Golgi stress disturbs cellular signaling and epigenetic regulation

Project description:The process of aging is associated with disturbed mineral homeostasis, such as zinc deficiency. Simultaneously, cellular response to external stimuli, including receptor signaling and DNA repair response diminishes, and epigenetic dysregulation occurs. The Golgi apparatus plays various roles in the cell; however, the effect of aging on the morphology and function of the Golgi apparatus and the impact of Golgi senescence in cellular activity remains unknown. In the present study, we found that Golgi stress is associated with senescent cell irresponsiveness to external stimuli. The senescent Golgi was associated with a disassembled microtubule network in the Golgi and perinuclear areas. These effects could be reproduced by disruption of the Golgi-associated microtubules or zinc depletion. To clarify the importance of Golgi-zinc homeostasis in more detail, the implications of the Golgi-zinc transporter ZIP13 were analyzed; Zip13-deficient mice Golgi exhibited morphology similar to that of senescent Golgi. Additionally, fibroblasts from Zip13-deficient mice showed dysregulation of DNA repair and cellular acetylation with downregulated nuclear translocation of p300, HDAC1/2, and p53 proteins, which are reminiscent characteristics of senescent cells. Our findings demonstrate the underlying reason for senescent cell irresponsiveness to various stimuli and highlight the importance of a zinc-rich diet during aging.

2024-08-26 | GSE235450 | GEO

DUX4 expression activates JNK and p38 MAP kinases in myoblasts

Project description:Facioscapulohumoral muscular dystrophy (FSHD) is caused by misexpression of the DUX4 transcription factor in skeletal muscle that results in transcriptional alterations, abnormal phenotypes, and cell death. To gain insight into the kinetics of DUX4-induced stresses, we activated DUX4 expression in myoblasts and performed longitudinal RNA sequencing paired with proteomics and phosphoproteomics. This analysis revealed changes in cellular physiology including DNA damage and altered mRNA splicing. Phosphoproteomic analysis uncovered widespread changes in protein phosphorylation rapidly following DUX4 induction indicating that alterations in kinase signaling may play a role in DUX4-mediated stress and cell death. Indeed, we demonstrate that two stress-responsive MAP kinase pathways, JNK and p38, are activated in response to DUX4 expression. Inhibition of each of these pathways ameliorated DUX4-mediated cell death in myoblasts. These findings uncover JNK as a novel pathway involved in DUX4-mediated cell death as well as provide additional insights into the role of the p38 pathway, a clinical target for the treatment of FSHD.

2022-07-05 | MSV000089812 | MassIVE

Actin-driven Golgi apparatus dispersal during collective migration of epithelial cells.

Project description:As a sedentary epithelium turns motile during wound healing, morphogenesis, and metastasis, the Golgi apparatus moves from an apical position, above the nucleus, to a basal position. This apical-to-basal repositioning of Golgi is critical for epithelial cell migration. Yet the molecular mechanism underlying it remains elusive, although microtubules are believed to play a role. Using live-cell and super-resolution imaging, we show that at the onset of collective migration of epithelial cells, Golgi stacks get dispersed to create an unpolarized transitional structure, and surprisingly, this dispersal process depends not on microtubules but on actin cytoskeleton. Golgi-actin interaction involves Arp2/3-driven actin projections emanating from the actin cortex, and a Golgi-localized actin elongation factor, MENA. While in sedentary epithelial cells, actin projections intermittently interact with the apically located Golgi, and the frequency of this event increases before the dispersion of Golgi stacks, at the onset of cell migration. Preventing Golgi-actin interaction with MENA-mutants eliminates Golgi dispersion and reduces the persistence of cell migration. Taken together, we show a process of actin-driven Golgi dispersion that is mechanistically different from the well-known Golgi apparatus fragmentation during mitosis and is essential for collective migration of epithelial cells.

| S-EPMC9245705 | biostudies-literature

Regulation of glial size by eicosapentaenoic acid through a novel Golgi apparatus mechanism.

Project description:Coordination of cell growth is essential for the development of the brain, but the molecular mechanisms underlying the regulation of glial and neuronal size are poorly understood. To investigate the mechanisms involved in glial size regulation, we used Caenorhabditis elegans amphid sheath (AMsh) glia as a model and show that a conserved cis-Golgi membrane protein eas-1/GOLT1B negatively regulates glial growth. We found that eas-1 inhibits a conserved E3 ubiquitin ligase rnf-145/RNF145, which, in turn, promotes nuclear activation of sbp-1/ SREBP, a key regulator of sterol and fatty acid synthesis, to restrict cell growth. At early developmental stages, rnf-145 in the cis-Golgi network inhibits sbp-1 activation to promote the growth of glia, and when animals reach the adult stage, this inhibition is released through an eas-1-dependent shuttling of rnf-145 from the cis-Golgi to the trans-Golgi network to stop glial growth. Furthermore, we identified long-chain polyunsaturated fatty acids (LC-PUFAs), especially eicosapentaenoic acid (EPA), as downstream products of the eas-1-rnf-145-sbp-1 pathway that functions to prevent the overgrowth of glia. Together, our findings reveal a novel and potentially conserved mechanism underlying glial size control.

| S-EPMC7793280 | biostudies-literature

Inhibition of Golgi apparatus glycosylation causes endoplasmic reticulum stress and decreased protein synthesis.

Project description:Nucleotide sugar transporters of the Golgi apparatus play an essential role in the glycosylation of proteins, lipids, and proteoglycans. Down-regulation of expression of the transporters for CMP-sialic acid, GDP-fucose, or both unexpectedly resulted in accumulation of glycoconjugates in the Golgi apparatus rather than in the plasma membrane. Pulse-chase experiments with radiolabeled sugars and amino acids showed decreased synthesis and secretion of both nonglycoproteins and glycoproteins. Further studies revealed that the above silencing induced endoplasmic reticulum stress and inhibited protein translation initiation. Together these results suggest that global inhibition of Golgi apparatus glycosylation may lead to important secondary metabolic changes, unrelated to glycosylation.

| S-EPMC2915696 | biostudies-literature

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