Shared and redundant proteins coordinate signal cross-talk between MAPK pathways in yeast
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE270781 | GEO | 2024/06/29
REPOSITORIES: GEO
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Project description:Schaber2012 - Hog pathway in yeast
The high osmolarity glycerol (HOG) pathway in the yeast Saccharomyces cerevisiae is one of the best-studied mitogen-activated protein kinase (MAPK) pathways and serves as a prototype signalling system for eukaryotes. This pathway is necessary and sufficient to adapt to high external osmolarity. A key component of this pathway is the stress-activated protein kinase (SAPK) Hog1, which is rapidly phosphorylated by the SAPK kinase Pbs2 upon hyper-osmotic shock, and which is the terminal kinase of two parallel signalling pathways, subsequently called the Sho1 branch and the Sln1 branch, respectively. Ensemble modelling (192 models) is used to study the yeast HOG pathway, a prototype for eukaryotic mitogen-activated kinase signalling systems. The best fit model (Model Nr.22: described here) provides new insights into the function of this system, some of which are then experimentally validated.
This model is described in the article:
Modelling reveals novel roles of two parallel signalling pathways and homeostatic feedbacks in yeast.
Schaber J, Baltanas R, Bush A, Klipp E, Colman-Lerner A.
Mol Syst Biol. 2012 Nov 13;8:622.
Abstract:
The high osmolarity glycerol (HOG) pathway in yeast serves as a prototype signalling system for eukaryotes. We used an unprecedented amount of data to parameterise 192 models capturing different hypotheses about molecular mechanisms underlying osmo-adaptation and selected a best approximating model. This model implied novel mechanisms regulating osmo-adaptation in yeast. The model suggested that (i) the main mechanism for osmo-adaptation is a fast and transient non-transcriptional Hog1-mediated activation of glycerol production, (ii) the transcriptional response serves to maintain an increased steady-state glycerol production with low steady-state Hog1 activity, and (iii) fast negative feedbacks of activated Hog1 on upstream signalling branches serves to stabilise adaptation response. The best approximating model also indicated that homoeostatic adaptive systems with two parallel redundant signalling branches show a more robust and faster response than single-branch systems. We corroborated this notion to a large extent by dedicated measurements of volume recovery in single cells. Our study also demonstrates that systematically testing a model ensemble against data has the potential to achieve a better and unbiased understanding of molecular mechanisms.
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2024-09-02 | BIOMD0000000429 | BioModels
Project description:The high osmolarity glycerol response (HOG) pathway plays a pivotal role in the stress response, virulence regulation, and differentiation of fungi, including Cryptococcus neoformans that causes fatal meningoencephalitis. Core signaling components of in the HOG pathway, including the Tco-Ypd1-Ssk1 phosphorelay system and the Ssk2-Pbs2-Hog1 MAPK module, have been elucidated but its downstream transcription factors remain unclear. Here we demonstrated that Atf1 with a basic leucine zipper domain is the transcription factor downstream of Hog1 in C. neoformans. We found that ATF1 expression was differentially regulated by oxidative damaging agents, mainly in a Hog1-dependent, but Mpk1-independent, manner. Interestingly, Atf1 not only promoted oxidative stress response and adaptation, but also played an opposing role to Hog1 in the process. Atf1 primarily localized to the nucleus under both unstressed and oxidative stress conditions in a Hog1-independent manner. Our data demonstrated that Atf1 promoted pheromone production and sexual differentiation under negative control by Hog1. Finally, a DNA microarray-based transcriptome analysis of the atf1∆ mutant under unstressed and oxidative stress conditions revealed that Atf1 regulated oxidative stress response genes, including a sulfiredoxin gene (SRX1). Intriguing, the array data further demonstrated that Atf1 modulated basal expression of genes involved in DNA repair and genotoxic stress response. Supporting this, we found that the atf1∆ mutant was highly sensitive to genotoxic agents. In conclusion, this study provided a further insight into the Hog1-dependent oxidative and genotoxic stress response and differentiation mechanism of C. neoformans.
2015-01-13 | GSE64871 | GEO
Project description:Cells respond to environmental stimuli via specialized signaling pathways. Concurrent stimuli trigger multiple pathways that integrate information, predominantly via protein phosphorylation. Budding yeast respond to NaCl and pheromone via two mitogen-activated protein kinase cascades, the high osmolarity and the mating pathways, respectively. To investigate signal integration between these pathways, we quantified the time-resolved phosphorylation site dynamics after pathway co-stimulation. Using shotgun mass spectrometry, we quantified 2536 phosphopeptides across 36 conditions. Our data indicate that NaCl and pheromone affect phosphorylation events within both pathways, which thus affect each other at more levels than anticipated, allowing for information exchange and signal integration. We observed a pheromone-induced down-regulation of Hog1 phosphorylation due to Gpd1, Ste20, Ptp2, Pbs2 and Ptc1. Distinct Ste20 and Pbs2 phosphosites responded differently to the two stimuli, suggesting these proteins as key mediators of the information exchange. A set of logic models was then used to assess the role of measured phosphopeptides in the crosstalk. Our results show that the integration of the response to different stimuli requires complex interconnections between signaling pathways.
2014-12-19 | PXD001445 | Pride
Project description:The high osmolarity glycerol response (HOG) pathway plays a pivotal role in the stress response, virulence regulation, and differentiation of fungi, including Cryptococcus neoformans that causes fatal meningoencephalitis. Core signaling components of in the HOG pathway, including the Tco-Ypd1-Ssk1 phosphorelay system and the Ssk2-Pbs2-Hog1 MAPK module, have been elucidated but its downstream transcription factors remain unclear. Here we demonstrated that Atf1 with a basic leucine zipper domain is the transcription factor downstream of Hog1 in C. neoformans. We found that ATF1 expression was differentially regulated by oxidative damaging agents, mainly in a Hog1-dependent, but Mpk1-independent, manner. Interestingly, Atf1 not only promoted oxidative stress response and adaptation, but also played an opposing role to Hog1 in the process. Atf1 primarily localized to the nucleus under both unstressed and oxidative stress conditions in a Hog1-independent manner. Our data demonstrated that Atf1 promoted pheromone production and sexual differentiation under negative control by Hog1. Finally, a DNA microarray-based transcriptome analysis of the atf1M-bM-^HM-^F mutant under unstressed and oxidative stress conditions revealed that Atf1 regulated oxidative stress response genes, including a sulfiredoxin gene (SRX1). Intriguing, the array data further demonstrated that Atf1 modulated basal expression of genes involved in DNA repair and genotoxic stress response. Supporting this, we found that the atf1M-bM-^HM-^F mutant was highly sensitive to genotoxic agents. In conclusion, this study provided a further insight into the Hog1-dependent oxidative and genotoxic stress response and differentiation mechanism of C. neoformans. There are more than 95% of genome homology between JEC21 and H99. Therefore 6 slides of JEC21 (Cryptococcus neoformans var. neoformans serotype D) 70-mer oligo are used in this analysis, 3 biological replicate experiments are performed, total RNAs are extracted 2 conditions (with or without treatment of Hydroten peroxide) from H99 (H99 Wild type strain (Cryptococcus neoformans var. grubii serotype A), and atf1M-NM-^T). We use the mixed all of total RNAs from this experiment as a control RNA. We use Cy3 as Sample dye and Cy5 as a control dye.
2015-01-13 | E-GEOD-64871 | biostudies-arrayexpress
Project description:Haploid budding yeast has two mating types, defined by the alleles of the MAT locus, MATa and MATα. Mating occurs when two haploid cells of opposite mating types signal to each other using reciprocal pheromones and receptors, polarize and grow towards each other, and eventually fuse to form a single diploid cell. The pheromones and receptors are necessary and sufficient to define a mating type, but other mating type-specific proteins make mating more efficient. We examined the role of these proteins by genetically engineering “transvestite” cells that swap the pheromone, pheromone receptor, and pheromone processing factors of one mating type for another. These cells can mate with each other, but their mating is inefficient. By characterizing their mating defects and examining their transcriptomes, we found Afb1 (a-factor barrier), a novel MATα-specific protein that interferes with a-factor, the pheromone secreted by MATa cells. We show that strong pheromone secretion is essential for efficient mating and that the weak mating of transvestites can be improved by boosting their pheromone production. Using synthetic biology, it is possible to characterize the factors that control efficiency in biological processes. In the case of budding yeast mating, selection for increased mating efficiency is likely to have continually boosted pheromone levels and the ability to discriminate between partners who make more (potentially fitter) and less (potentially less fit) pheromones. This sensitivity to which partner makes more pheromone comes at a cost: it means mating is not robust in situations where all potential partners make less pheromone.
2014-01-07 | GSE49372 | GEO
Project description:Candida glabrata is an important and increasingly common pathogen of humans, particularly in immunocompromised hosts. Despite this, little is known about how this fungus causes disease. Here, we applied RNA sequencing and an in vivo invasive infection model to identify the attributes that allow this organism to infect hosts. Fungal transcriptomes show a dramatic increase in the expression of Fus3 and Kss1, two mitogen-activated protein kinases (MAPKs), during invasive infection. We further demonstrate that they are both highly induced under a combination of serum and high CO2 condition. Deletion of both FUS3 and KSS1, but neither gene alone, results in a reduced fungal burden in organs, as well as in gastrointestinal tract in the DSS (Dextran Sulfate Sodium)-induced colitis model. Similarly, the defect in persistence in macrophages and attenuated adhesion to epithelial cells are observed when FUS3 and KSS1 are both disrupted. The fus3 kss1 double mutant also displays defects in the induction of virulence attributes such as genes required for iron acquisition and adhesion, and in the anti-fungal drug tolerance. The putative downstream transcription factors Ste12(1), Ste12(2), Tec1 and Tec2 are found to be involved in the regulation of these virulence attributes. Collectively, our study indicates that an evolutionary conserved MAPK pathway which regulates mating and filamentous growth in Saccharomyces cerevisiae, is critical for C. glabrata pathogenicity.
2024-10-16 | GSE279281 | GEO
Project description:In budding yeast, this signaling pathway— the high-osmolarity glycerol (HOG) response —culminates in dual phosphorylation and nuclear translocation of the MAPK, Hog1 (ortholog of mammalian p38/SAPK). Induction of at least 50 genes requires nuclear Hog1, implying that transcriptional up-regulation is necessary to cope with hyperosmotic stress. Contrary to this expectation, we found that cells lacking the karyopherin (Nmd5) required for Hog1 nuclear import or in which Hog1 was permanently anchored at the plasma membrane(HOG1-CCAAX) (or both) withstood hyperosmotic challenge by three different solutes (1 M sorbitol, KCl or NaCl). In cells where activated Hog1 is excluded from the nucleus, there was little change in transcriptional program after exposure to hyperosmotic shock (comparable to hog1∆ cells), as judged by examining several diagnostic mRNAs and by global transcript measurements using microarrays. Systematic genetic analysis ruled out the need for any transcription factor known to be influenced by Hog1 (Hot1, Msn2, Msn4, Sko1 and Smp1). Keywords: Time course of stress response gene expression array
2008-06-01 | GSE8703 | GEO
Project description:Haploid budding yeast has two mating types, defined by the alleles of the MAT locus, MATa and MATM-NM-1. Mating occurs when two haploid cells of opposite mating types signal to each other using reciprocal pheromones and receptors, polarize and grow towards each other, and eventually fuse to form a single diploid cell. The pheromones and receptors are necessary and sufficient to define a mating type, but other mating type-specific proteins make mating more efficient. We examined the role of these proteins by genetically engineering M-bM-^@M-^\transvestiteM-bM-^@M-^] cells that swap the pheromone, pheromone receptor, and pheromone processing factors of one mating type for another. These cells can mate with each other, but their mating is inefficient. By characterizing their mating defects and examining their transcriptomes, we found Afb1 (a-factor barrier), a novel MATM-NM-1-specific protein that interferes with a-factor, the pheromone secreted by MATa cells. We show that strong pheromone secretion is essential for efficient mating and that the weak mating of transvestites can be improved by boosting their pheromone production. Using synthetic biology, it is possible to characterize the factors that control efficiency in biological processes. In the case of budding yeast mating, selection for increased mating efficiency is likely to have continually boosted pheromone levels and the ability to discriminate between partners who make more (potentially fitter) and less (potentially less fit) pheromones. This sensitivity to which partner makes more pheromone comes at a cost: it means mating is not robust in situations where all potential partners make less pheromone. 4 conditions were analysed, each with 3 biological replicates. The conditions were unstimulated MATa cells in YPD. Stimulated MATa cells in YPD+10nM M-NM-1-factor. Unstimulated MATM-NM-1 cells in YPD. Stimulated MATM-NM-1 cells in YPD+10nM M-NM-1-factor.
2014-01-07 | E-GEOD-49372 | biostudies-arrayexpress
Project description:The basis for commitment to cell division in late G1 phase, called Start in yeast and the Restriction Point in metazoans, is a critical but still poorly understood aspect of eukaryotic cell proliferation. All eukaryotic cells must grow to a critical cell size before commitment to division occurs. This size threshold couples cell growth to division and thereby establishes long-term size homeostasis. Here, to address the problem of cell size control across different species, we performed the first quantitative survey of the size phenome in the pathogenic yeast Candida albicans by focusing on mutants of transcriptional regulators and kinases. We investigate one of the divergent size regulatory pathways in C. albicans, the p38/HOG MAPK module, to uncover a novel stress-independent function for the HOG module in size control. We show that Hog1 inhibits G1/S transcription to delay the G1/S transition and that Hog1 also controls ribosome biogenesis gene expression. These results suggest that Hog1 represents a critical and previously unsuspected nexus between the growth and division machineries. Our study thus delineates the overall genetic basis for size control in C. albicans and identifies, to our knowledge, the first specific conduit that couples cell growth to cell division.
2019-02-20 | GSE126732 | GEO
Project description:Mating pheromone is the best-known fungal paracrine signal whose essentiality in determining sexual reproduction has been recognized since six decades ago. We demonstrate that the pheromone cannot induce mating response during unisexual mating due to the lack of a compatible receptor from the same unisexual population. We identify a quorum sensing (QS) peptide Qsp1 in place of pheromone as a specific intercellular signal directing Cryptococcus unisexual reproduction. A typical zinc finger regulator Cqs2 as the master regulator of QS signaling induces unisexual reproduction in response to Qsp1. Collectively, these data demonstrate that QS activation rather than pheromone induction as the pivotal social control mechanism underlies unisexual reproduction in C .neoformans.
2018-05-15 | GSE94091 | GEO