Metabolic Respiration Induces AMPK- and Ire1p-Dependent Activation of the p38-Type HOG MAPK Pathway
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE61783 | GEO | 2014/09/26
SECONDARY ACCESSION(S): PRJNA262096
REPOSITORIES: GEO
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Project description:In fungal species, differentiation to the filamentous/hyphal cell type is critical for entry into host cells and virulence. Comparative RNA sequencing was used to explore the pathways that regulate differentiation to the filamentous cell type in yeast. This approach uncovered a role for the stress-response MAPK pathway, HOG, during the increased metabolic respiration that induces filamentous growth. In this context, the AMPK Snf1p and ER stress kinase Ire1p regulated the HOG pathway. Cross-modulation between the HOG and filamentous growth (ERK-type) MAPK pathways optimized the differentiation response. The regulatory circuit described here may extend to behaviors in metazoans. Comparison of expression patterns of wild-type and mutant yeast cells grown in salt, tunicamycin or galactose by comparative RNA sequencing analysis.
2014-09-26 | E-GEOD-61783 | biostudies-arrayexpress
Project description:Evolutionarily conserved mitogen activated protein kinase (MAPK) pathways regulate the response to stress as well as cell differentiation. In Saccharomyces cerevisiae, growth in non-preferred carbon sources (like galactose) induces differentiation to the filamentous cell type through an extracellular-signal regulated kinase (ERK)-type MAPK pathway. The filamentous growth MAPK pathway shares components with a p38-type High Osmolarity Glycerol response (HOG) pathway, which regulates the response to changes in osmolarity. To determine the extent of functional overlap between the MAPK pathways, comparative RNA sequencing was performed, which uncovered an unexpected role for the HOG pathway in regulating the response to growth in galactose. The HOG pathway was induced during growth in galactose, which required the nutrient regulatory AMP-dependent protein kinase (AMPK) Snf1p, an intact respiratory chain, and a functional tricarboxylic acid (TCA) cycle. The unfolded protein response (UPR) kinase Ire1p was also required for HOG pathway activation in this context. Thus, the filamentous growth and HOG pathways are both active during growth in galactose. The two pathways redundantly promoted growth in galactose, but paradoxically, they also inhibited each other's activities. Such cross-modulation was critical to optimize the differentiation response. The human fungal pathogen Candida albicans showed a similar regulatory circuit. Thus, an evolutionarily conserved regulatory axis links metabolic respiration and AMPK to Ire1p, which regulates a differentiation response involving the modulated activity of ERK and p38 MAPK pathways.
| S-EPMC4214603 | biostudies-literature
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:Dimorphic fungi are temperature-sensitive organisms that couple their cell shape with their environment. One of these fungi, Histoplasma capsulatum, exists as both a soil-dwelling hypha and a host-associated yeast. Here we examine the role of the previously uncharacterized gene MSB2 in filamentous growth. We performed a genetic screen to identify insertion mutants that are unable to transition from the yeast form to the hyphal form. One yeast-locked mutant has an insertion upstream of the MSB2 gene. This mutant strain (SG1) fails to express MSB2, whose ortholog in the model yeast Saccharomyces cerevisiae is a known signaling component in the high osmolarity glycerol (HOG) pathway and filamentous growth (FG) pathway. Here, we profiled gene expression by RNA-seq to characterize transcriptional differences between wild type and msb2 mutant strains during the yeast to hyphal transition.
2019-09-30 | GSE124292 | GEO
Project description:The ability to sense and adapt to a hostile host environment is a crucial element for virulence of pathogenic fungi, including Cryptococcus neoformans. These cellular responses are evoked by diverse signaling cascades, including the stress-activated HOG pathway. Despite previous analysis of central components of the HOG pathway, its downstream signaling network is poorly characterized in C. neoformans. Here we performed comparative transcriptome analysis with HOG signaling mutants to explore stress-regulated genes and their correlation with the HOG pathway in C. neoformans. In this study we not only provide important insights into remodeling patterns of global gene expression for counteracting external stresses, but also elucidated novel characteristics of the HOG pathway in C. neoformans. First, inhibition of the HOG pathway increases expression of ergosterol biosynthesis genes and cellular ergosterol content, conferring a striking synergistic antifungal activity with amphotericin B and providing an excellent opportunity to develop a novel therapeutic method for treatment of cryptococcosis. Second, a number of cadmium-sensitive genes are differentially regulated by the HOG pathway, and their mutation causes resistance to cadmium. Finally, we have discovered novel stress-defense and HOG-dependent genes, which encodes a sodium/potassium efflux pump, protein kinase, multidrug transporter system, and elements of the ubiquitin-dependent system.
2009-06-27 | GSE16692 | GEO
Project description:The ability to sense and adapt to a hostile host environment is a crucial element for virulence of pathogenic fungi, including Cryptococcus neoformans. These cellular responses are evoked by diverse signaling cascades, including the stress-activated HOG pathway. Despite previous analysis of central components of the HOG pathway, its downstream signaling network is poorly characterized in C. neoformans. Here we performed comparative transcriptome analysis with HOG signaling mutants to explore stress-regulated genes and their correlation with the HOG pathway in C. neoformans. In this study we not only provide important insights into remodeling patterns of global gene expression for counteracting external stresses, but also elucidated novel characteristics of the HOG pathway in C. neoformans. First, inhibition of the HOG pathway increases expression of ergosterol biosynthesis genes and cellular ergosterol content, conferring a striking synergistic antifungal activity with amphotericin B and providing an excellent opportunity to develop a novel therapeutic method for treatment of cryptococcosis. Second, a number of cadmium-sensitive genes are differentially regulated by the HOG pathway, and their mutation causes resistance to cadmium. Finally, we have discovered novel stress-defense and HOG-dependent genes, which encodes a sodium/potassium efflux pump, protein kinase, multidrug transporter system, and elements of the ubiquitin-dependent system. There is more than 95% genome homology between JEC21 (Cryptococcus neoformans var. neoformans serotype D) and H99 (Cryptococcus neoformans var. grubii serotype A). Therefore, 100 slides of JEC21 70-mer oligo arrays are used in this analysis. 3 biological replicate experiments are performed. Total RNAs are extracted under 3 conditions (1M NaCl, 20ug/ul Fludioxonil, 2.5mM Hydrogen peroxide) at 3 time points (0time, 30min, 60min) with 4 strains from H99 (wild type, hog1Î , ssk1Î , skn7Î). We use a mix of all the total RNAs from this experiment as the control RNA. We use Cy5 as the sample dye and Cy3 as the control dye. Several samples are dye swapped.
2010-05-17 | E-GEOD-16692 | biostudies-arrayexpress
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: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:HOG cells were plated in 6-well plates (0.5 × 10^6 cells per well). 24 hours later, HOG-EV or HOG-R132H cells were treated for 24 hours with 10 nM BAY 2402234 or DMSO. Cells were then harvested for LC-MS analysis.
2022-07-14 | ST002231 | MetabolomicsWorkbench