Hog1/p38 regulates the integrated stress response (ISR) and global transcriptomic changes in C. neoformans during oxidative stress.
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PROVIDER: PRJNA1263785 | ENA |
REPOSITORIES: ENA
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Project description:Cryptococcus neoformans is an opportunistic fungal pathogen that is responsible for an estimated 112,000 deaths per year. We studied the role of the Hog1/p38 and Gcn2 signal transduction pathways during adaptation of C. neoformans to oxidative stress, a physiologically relevant stressor during infection. Using a combination of molecular assays and RNA-sequencing analysis in Hog1-, Gcn2- and double-deleted mutants, we identify shared targets of these pathways, and investigate a negative feedback loop that regulates induction of the integrated stress response (ISR). We found that simultaneous loss of Hog1 and Gcn2 profoundly impacts the ability of C. neoformans to tolerate oxidative stress. We also show that Hog1 regulates induction of the ISR, and that the Hog1 and Gcn2 pathways converge on repression of abundant, pro-growth mRNA, a key step in translatome reprogramming. Our results establish Hog1 and Gcn2 as key regulators of the response to oxidative stress, and demonstrate that the interplay between these pathways is critical for ROS tolerance in C. neoformans. More broadly, our results demonstrate the extent to which signaling via Hog1/p38 and Gcn2 are linked, and point to extensive recalibration of the cellular signaling apparatus when one of these pathways is disrupted.
2025-08-15 | GSE297408 | 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: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: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 The transcriptomes' of HOG1-GFP, hog1del, and HOG1-CCAAX strains before and after 60 min hyperosmotic shock with 1M sorbitol at 25C were compared. Three biological replicates were done, with the first biological replicate done in technical triplicate, and the final two biological replicates beind done in technical duplicate by in slide duplication of features. Several supplementary files attached to the Series are summarized below: GSE8703 B1, B2, B3 Tscombined_matrix files show the averages of the technical replicates for each biological replicate. GSE8703 B1, B2, B3 norm_to_0_matrix files show the fold change over the time course (log2 time 60 - log2 time 0) for each of the three strains in each biological replicate. GSE8703 Figure_S6 shows the 30 genes with the most significant difference between the HOG1-GFP strain and the hog1del strain as determined by SAM. Genes were identified as: >3 fold induction in HOG1-GFP over 60 minute hyperosmotic shock and <3 fold induction in hog1del over 60 minute hyperosmotic shock.
2008-06-01 | E-GEOD-8703 | biostudies-arrayexpress
Project description:Based on studies in S. pombe (Chen et al., 2003), we predicted that conditions which activate C. albicans Hog1 would result in the induction of a common set of genes that are regulated by this SAPK (Smith et al., 2004). Hence in this study we compared the global transcriptional responses of wild-type and hog1 C. albicans cells to environmental stresses that are known to activate the Hog1 SAPK. We compared the homozygous hog1/hog1 null mutant (JC50) with the isogenic HOG1 reintegrant (hog1/hog1/HOG1: JC52) because this controlled for any secondary mutations that might have been introduced during the construction of the null mutant. We have shown that this reintegrant is indistinguishable from its parental wild-type strain RM1000 (HOG1/HOG1) with respect to their stress phenotypes (Smith et al., 2004) and their expression of stress genes (Supplementary Data). Three conditions were chosen for transcript profiling: osmotic stress imposed by 0.3 M NaCl, oxidative stress imposed by 5 mM H2O2, and heavy metal stress imposed by 0.5 mM CdSO4. Each of these treatments stimulates the phosphorylation and nuclear accumulation of this Hog1 SAPK within a 10-min time frame (Smith et al., 2004). Furthermore, significant differences in stress regulated gene expression are observed within this time scale (Enjalbert et al., 2003; Smith et al., 2004). Hence, we analyzed the C. albicans transcriptome after a 10-min exposure to each stress condition. Although some stress genes might be missed by analyzing a single time point, most C. albicans stress genes are induced within 10 min (Enjalbert et al., 2003). At least four independent biological replicates were analyzed for each condition
2007-07-05 | E-MEXP-1134 | biostudies-arrayexpress
Project description:Cells are subjected to dramatic changes on gene expression upon environmental changes. Stress causes a general down-regulation of gene expression together with the induction of a set of stress-responsive genes. Genome wide localisation studies showed major changes on Pol II localisation towards stress-responsive genes in contrast to housekeeping genes. Pol II relocalisation requires of the Hog1 SAPK, which also associates at stress-responsive loci. Chromatin structure was not significantly altered upon stress except for those genes that displayed Hog1 association. Together, Hog1 serves to bypass the general down-regulation of gene expression by targeting RNA Pol II machinery and inducing chromatin remodeling at stress-responsive loci.
2012-10-30 | GSE41494 | GEO
Project description:The stress-activated protein kinase Hog1 is best known for its role in osmotic stress but is also activated by a variety of mechanistically distinct environmental stressors including heat shock, ER stress, and arsenic. In the osmotic stress response, the signal is sensed upstream and relayed to Hog1 via a kinase cascade. Here we identify a novel mode of Hog1 function whereby Hog1 senses arsenic though direct physical interaction requiring three conserved cysteine residues located adjacent to the catalytic loop. These residues are essential for Hog1's role in protecting against arsenic, but completely dispensable for osmotic stress, and mediate Hog1's cellular localization upon arsenic exposure. Hog1 in turn regulates arsenic detoxification by phosphorylating the transcription factor Yap8, promoting its nuclear localization, and stimulating transcription of its only known targets, Arr2 and Arr3, which promote arsenic efflux. Arsenic binding was also observed with the related human kinases Erk1 and Erk2, suggesting that this may be a conserved aspect of this kinase family. These data provide a mechanistic basis for understanding how stress-activated kinases can sense individual threats and carry out highly specific adaptive responses.
2019-12-04 | PXD015325 | Pride
Project description:Cells are subjected to dramatic changes on gene expression upon environmental changes. Stress causes a general down-regulation of gene expression together with the induction of a set of stress-responsive genes. Genome wide localisation studies showed major changes on Pol II localisation towards stress-responsive genes in contrast to housekeeping genes. Pol II relocalisation requires of the Hog1 SAPK, which also associates at stress-responsive loci. Chromatin structure was not significantly altered upon stress except for those genes that displayed Hog1 association. Together, Hog1 serves to bypass the general down-regulation of gene expression by targeting RNA Pol II machinery and inducing chromatin remodeling at stress-responsive loci. Hog1 and Pol II ChIP-Seq and Mnase-Seq experiments in both strains WT and Hog1 mutant, for 2 conditions: Exposed and not exposed to osmostress
2012-10-30 | E-GEOD-41494 | biostudies-arrayexpress
Project description:Hog1 bypasses stress-mediated downregulation of transcription by PolII redistribution and chromatin remodeling Keyword: genetic modification
2012-10-30 | GSE41451 | GEO