Functional dissection of the regulatory mechanism of the atypical AP-1-like transcription factor, Yap1, in Cryptococcus neoformans
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ABSTRACT:
PROVIDER: PRJNA563833 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR10065422_1.fastq.gz | Fastqsanger.gz | |||
| SRR10065422_2.fastq.gz | Fastqsanger.gz | |||
| SRR10065423_1.fastq.gz | Fastqsanger.gz | |||
| SRR10065423_2.fastq.gz | Fastqsanger.gz | |||
| SRR10065424_1.fastq.gz | Fastqsanger.gz |
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Project description:AP-1 like transcription factors play evolutionarily conserved roles in oxidative stress responses as redox sensors in eukaryotes. In this study, we aim to elucidate the regulatory mechanism of an atypical yeast AP-1 like protein, Yap1, in the stress response and virulence of Cryptococcus neoformans. YAP1 expression was induced not only by oxidative stresses, such as H2O2 and diamide, but also by other environmental stresses, such as osmotic and membrane destabilizing stresses. Supporting these data, Yap1 was involved in osmotic and membrane stress responses as well as oxidative stress responses. Pleiotropic roles of Yap1 in diverse biological processes were supported by transcriptome analysis data showing that more than 162 genes are differentially regulated by Yap1. This analysis also provided a clue that Yap1 is involved in carbohydrate metabolism and indeed we found that Yap1 promotes cellular resistance to toxic cellular metabolites produced during glycolysis, such as methylglyoxal. Finally, we demonstrated that Yap1 played a minor role in survival of C. neoformans within hosts.
2019-11-07 | GSE136832 | GEO
Project description:YAP1 complexes separation with affinity purification (AP) coupled to BNPAGE
2023-03-04 | PXD030061 | Pride
Project description:AP-1-like transcription factors play evolutionarily conserved roles as redox sensors in eukaryotic oxidative stress responses. In this study, we aimed to elucidate the regulatory mechanism of an atypical yeast AP-1-like protein, Yap1, in the stress response and virulence of Cryptococcus neoformansYAP1 expression was induced and involved not only by oxidative stresses, such as H2O2 and diamide, but also by other environmental stresses, such as osmotic and membrane-destabilizing stresses. Yap1 was distributed throughout both the cytoplasm and the nucleus under basal conditions and more enriched within the nucleus in response to diamide but not to other stresses. Deletion of the C-terminal cysteine-rich domain (c-CRD), where the nuclear export signal resides, increased nuclear enrichment of Yap1 under basal conditions and altered resistance to oxidative stresses but did not affect the role of Yap1 in other stress responses and cellular functions. As a potential upstream regulator of Yap1, we discovered that Mpk1 is positively involved, but Hog1 is mostly dispensable. Pleiotropic roles for Yap1 in diverse biological processes were supported by transcriptome data showing that 162 genes are differentially regulated by Yap1, with further analysis revealing that Yap1 promotes cellular resistance to toxic cellular metabolites produced during glycolysis, such as methylglyoxal. Finally, we demonstrated that Yap1 plays a minor role in the survival of C. neoformans within hosts.IMPORTANCE The human meningitis fungal pathogen, Cryptococcus neoformans, contains the atypical yeast AP-1-like protein Yap1. Yap1 lacks an N-terminal cysteine-rich domain (n-CRD), which is present in other fungal Yap1 orthologs, but has a C-terminal cysteine-rich domain (c-CRD). However, the role of c-CRD and its regulatory mechanism remain unknown. Here, we report that Yap1 is transcriptionally regulated in response to oxidative, osmotic, and membrane-destabilizing stresses partly in an Mpk1-dependent manner, supporting its role in stress resistance. The c-CRD domain contributed to the role of Yap1 only in resistance to certain oxidative stresses and azole drugs but not in other cellular functions. Yap1 has a minor role in the survival of C. neoformans in a murine model of systemic cryptococcosis.
| S-EPMC6887862 | biostudies-literature
Project description:Proteins which act as histone chaperones ensure genomic integrity during routine processes such as DNA replication and transcription as well as DNA repair upon damage. Herein, we identify a nuclear J domain protein, Dnj4, which interacts with histones 3 and 4 as well as Hsp71 as demonstrated in an AP-MS experiment suggesting that it integrates the heat shock chaperone machinery into histone chaperoning. In support of this, a deletion mutant lacking DNJ4 had higher levels of DNA damage than the wild type or complemented strains and was hypersensitive to DNA damaging agents. The transcriptional response to DNA damage in a mutant lacking DNJ4 was impaired. Genes related to DNA damage and iron homeostasis functions were up-regulated in the wild type strain in response to hydroxyurea treatment, however their up-regulation was either absent or reduced in a dnj4∆ mutant. Accordingly, excess iron rescued the mutant’s growth in response to hydroxyurea treatment. Iron homeostasis is crucial for virulence in Cryptococcus neoformans, however Dnj4 was found to be dispensable for virulence in a mouse model of cryptococcosis. Finally, we confirmed a conserved role of Dnj4 in histone chaperoning by expressing it in S. cerevisiae and showing that it disrupted endogenous histone chaperoning. Altogether, this study highlights the importance of a JDP co-chaperone in histone chaperoning in C. neoformans.
2021-12-15 | PXD028087 | Pride
Project description:In this project we investigated the topological composition of ternary complex PTPN14/LATS1/PTPN14. For this purpose, we performed affinity purification with Strep tag of Strep-HA YAP1 and subsequent XL reaction.
2023-03-04 | PXD039440 | Pride
Project description:Cryptococcus neoformans is an opportunistic basidiomycete pathogen that is a major etiological agent of fungal meningoencephalitis leading to more than 180,000 deaths worldwide annually. For this pathogen, the polysaccharide capsule is a key virulence factor, which interferes with the phagocytosis by host innate immune cells, but its complex signaling networks remain elusive. In this study, we systematically analyzed capsule biosynthesis and signaling networks by using C. neoformans transcription factor (TF) and kinase mutant libraries under diverse capsule-inducing conditions, such as Dulbecco’s Modified Eagle’s (DME), Littman’s medium (LIT) and fetal bovine serum (FBS) medium. We found that deletion of GAT201, YAP1, BZP4, and ADA2 consistently causes capsule production defects in all tested media, indicating that they are capsule-regulating core TFs. Epistatic and expression analysis showed that Yap1 and Ada2 control Gat201 upstream, whereas Bzp4 and Gat201 regulate capsule production independently. We next searched for potential upstream kinases and found that mutants deleted of PKA1, BUD32, POS5, IRE1 or CDC2801 showed reduced capsule production under all three capsule induction conditions, whereas mutants deleted of HOG1 and IRK5 displayed enhanced capsule production. Notably, Pka1 and Irk5 controls induction of GAT201 and BZP4, respectively, under capsule induction condition. Finally, we monitored transcriptome profiles governed by Bzp4, Gat201, and Ada2 under capsule-inducing condition and demonstrated that these TFs regulate redundant and unique sets of downstream target genes. In conclusion, this study provides further insight into the complex regulatory mechanism of capsule production related signaling pathways in C. neoformans.
2022-10-18 | GSE208163 | GEO
Project description:The opportunistic fungal pathogen Cryptococcus neoformans must adapt to the mammalian environment to establish an infection. Proteins facilitating adaptation to novel environments, such as chaperones, may be required for virulence. In this study, we identified a novel mitochondrial co-chaperone, Mrj1, necessary for virulence in C. neoformans. The mrj1∆ and J-domain inactivated mutants had general growth defects, and were deficient in two major virulence factors, thermotolerance and capsule elaboration. The latter phenotype was associated with cell wall changes and increased capsular polysaccharide shedding. Accordingly, the mrj1∆ mutant was avirulent in a murine model of cryptococcosis. Mrj1 has a mitochondrial localization and co-immunoprecipitated with Qcr2, a core component of complex III of the ETC (Electron Transport Chain). The mrj1 mutants were deficient in mitochondrial functions including growth on alternative carbon sources, growth without iron, and mitochondrial polarization. They were also insensitive to complex III inhibitors and hypersensitive to an alternative oxidase (AOX) inhibitor suggesting that Mrj1 functions in respiration. In support of this conclusion, mrj1 mutants also had elevated basal oxygen consumption rates which were completely abolished by the addition of the AOX inhibitor, confirming that Mrj1 is required for mitochondrial respiration through complexes III and IV. Furthermore, inhibition of complex III phenocopied the capsule and cell wall defects of the mrj1 mutants. Taken together, these results indicate that Mrj1 is required for normal mitochondrial respiration, a key aspect of adaptation to the host environment and virulence.
2020-06-12 | PXD013659 | Pride
Project description:In order to define YAP1-specific gene expression patterns in gastric cancer, the constitutively active mutant YAP1 (YAP1-S127A) was over-expressed in MKN45 gastric cancer cells. Defined gene expression signature was later used to stratify gastric cancer patients according to the presence of the YAP1-activated signature. Three groups of samples are included: 1. Mock control; 2. Vector control; 3. YAP-S127A expression. Gene expression profiles of YAP-S127A mutant-expressing cells were compared to that of mock and vector control. Experiments were done in MKN45 gastric cancer cells.
2013-10-01 | E-GEOD-41387 | biostudies-arrayexpress
Project description:Doxycycline-inducible YAP1 S127A-driven rhabdomyosarcoma (RMS) tumors, control skeletal muscle and regressed tumors following YAP1 normalization by doxycycline withdrawal were compared to determine the YAP1-regulated gene expression profile relevant to RMS formation. To characterize the role of YAP1 in embryonal RMS at the molecular level and identify a gene signature for YAP1 activity readout, we compared the gene expression profiles of our YAP1-driven ERMS with control donor skeletal muscle (SKM) and doxycycline-withdrawn regressing tumors by microarray (doxycycline withdrawal for 3 or 6 days; OFF3 and OFF6, respectively). We next extracted a list of genes regulated by YAP1 in our YAP1-driven ERMS tumors (TUM) versus the 3 other conditions: skeletal muscle control (SKM), Doxycycline-withdrawn 3 days (OFF3) and 6 days (OFF6). The overlap between the 3 lists identified a subset of 633 common upregulated genes, named the YAP1-ERMS_UP signature, as well as 249 common downregulated genes, termed the YAP1-ERMS_DOWN signature. Proliferative pathways and transcriptional targets of E2F factors were highlighted in the YAP1-ERMS_UP genes, while muscle differentiation and trancriptional targets of myogenic factors Myod1 and Mef2 were highlighted in the YAP1-ERMS_DOWN genes. Tumor regression conditions (OFF3 days; OFF6 days) as well as control muscle (CTL) were compared with tumors at day 0 of doxycycline withdrawal (TUM). 3 samples for each conditions were used.
2014-08-12 | E-GEOD-47198 | biostudies-arrayexpress
Project description:In this project we investigated the effect of YAP1 mutations on the interactome. We investigate the effect of S61A, S109A, S127A, S138A, S143A, S367A, 5SA.
2023-03-04 | PXD039445 | Pride