Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

WT vs rim101 mutant gene expression under capsule inducing conditions

ABSTRACT: Cryptococcus neoformans is a prevalent human fungal pathogen that must survive within various tissues in order to establish a human infection. We have identified the C. neoformans Rim101 transcription factor, a highly conserved pH-response regulator in many fungal species. The rim101- mutant strain displays growth defects similar to other fungal species in the presence of alkaline pH, increased salt concentrations, and iron limitation. However, the rim101- strain is also characterized by a striking defect in capsule, an important virulence-associated phenotype. This capsular defect is likely due to alterations in polysaccharide attachment to the cell surface, not in polysaccharide biosynthesis. In contrast to many other C. neoformans capsule-defective strains, the rim101- mutant is hypervirulent in animal models of cryptococcosis. Whereas Rim101 activation in other fungal species occurs through the conserved Rim pathway, we demonstrate that C. neoformans Rim101 is also activated by the cAMP/PKA pathway. We report here that C. neoformans uses PKA and the Rim pathway to regulate the localization, activation, and processing of the Rim101 transcription factor. We also demonstrate specific host- relevant activating conditions for Rim101 cleavage, showing that C. neoformans has co-opted conserved signaling pathways to respond to the specific niche within the infected host. These results establish a novel mechanism for Rim101 activation and the integration of two conserved signaling cascades in response to host environmental conditions.

ORGANISM(S): Cryptococcus neoformans var. neoformans Cryptococcus neoformans var. grubii

PROVIDER: GSE23929 | GEO | 2010/09/04

SECONDARY ACCESSION(S): PRJNA130327

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Proteomic profiling of Cryptococcus neoformans

Project description:The opportunistic fungal pathogen Cryptococcus neoformans causes life-threatening meningitis in immunocompromised individuals. The expression of virulence factors including capsule and melanin is in part regulated by the cyclic-AMP/Protein Kinase A (PKA) signal transduction pathway. In this study, we investogated the influence of PKA on the composition of the intracellular proteome to obatin a comprehensive understanding of the regulation that underpins virulence. Through quantitative proteomics, enrichment and bioinformatic analyses, and an interactome study, we discovered a conserved pattern of PKA regulation for proteins associated with translation, the proteasome, metabolism, amino acid biosynthesis, and virulence-related functions. PKA regulation of the ubiquitin-proteasome pathway in C. neoformans showed a striking parallel with connections between PKA and protein degradation in chronic neurodegenerative disorders and other human diseases. Further investigation using the proteasome inhibitor bortezomib revealed an impact on capsule production and fungal growth. These results prompted additional studies of the antifungal activity of bortezomib in the context of cAMP signlaing and in combination with fluconazole. Taken together, the data suggest a model whereby PKA activation causes a shift in proteostasis and the function of the endoplasmic reticulum to support the synthesis and export of capsule polysaccharide. Overall, this study revealed a remarkably broad and conserved influence of the cAMP/PKA pathway on the proteome, and identified proteostasis as a potential therapeutic target for the treatment of cryptococcosis.

2016-01-18 | PXD002727 | Pride

How host-like signals drive gene expression and gene expression drives capsule growth in Cryptococcus neoformans [ep_pert]

2023-08-02 | GSE226651 | GEO

How host-like signals drive gene expression and gene expression drives capsule growth in Cryptococcus neoformans [ep_titration]

Project description:Cryptococcus neoformans is a fungal pathogen with a polysaccharide capsule that becomes greatly enlarged in the mammalian host and during in vitro growth in response to host-like conditions. To understand how individual host-like signals affect capsule size and gene expression, we grew cells wild-type KN99 cells with either no added cyclic AMP (cAMP), 1.1 mM, 1.8 mM, 3.3 mM, 11 mM, or 20 mM cAMP. capsule thickness at 1440 min. We also took samples for RNA-Seq at 30, 90, 180, 1440 minutes and carried out RNA-Seq in quadruplicate. We also measured capsule thickness at 1440 min.

2023-08-02 | GSE226637 | GEO

Proteome profiling of virulence-associated CipC from Cryptococcus neoformans

Project description:Cryptococcus neoformans is a human fungal pathogen found ubiquitously within the environment and associated with infection of primarily immunocompromised individuals. Without the activation of an effective immune response, the pathogen can survive, proliferate, and disseminate throughout the host through the action of diverse virulence factors. These virulence factors include a polysaccharide capsule to protect the fungus from phagocytosis by macrophages, melanin production to neutralize reactive oxygen species, thermotolerance to survive at human physiological temperatures, and extracellular enzymes for host tissue degradation and invasion. We previously used mass spectrometry-based proteomics to explore the production of fungal virulence factors during infection using in vitro (macrophages) and in vivo (murine) models of disease. Based on our studies, we investigated the proteome response of C. neoformans upon disruption of CipC, a virulence-associated fungal protein.

2024-10-13 | PXD056761 | Pride

How host-like signals drive gene expression and gene expression drives capsule growth in Cryptococcus neoformans [ep_wt]

Project description:Cryptococcus neoformans is a fungal pathogen with a polysaccharide capsule that becomes greatly enlarged in the mammalian host and during in vitro growth in response to host-like conditions. To understand how individual host-like signals affect capsule size and gene expression, we grew cells with and without all combinations of 5 signals suspected of affecting capsule size: Tissue-culture medium (DMEM or RPMI), temperature (37°C), CO2 (5%), and the addition of HEPES buffer. For each combination of conditions, we grew cultures with or without exogenous cAMP, and sampled cells for RNA-Seq at 0, 30, 90, 180, 1440 minutes and for measurement of capsule thickness at 1440 min. We also took samples for RNA-Seq at 30, 90, 180, 1440 minutes and carried out RNA-Seq in quadruplicate.

2023-08-02 | GSE226255 | GEO

Unraveling capsule biosynthesis and signaling networks in Cryptococcus neoformans

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

Differentially expressed genes of cir1 mutants in low iron or high iron medium

Project description:Iron overload is known to exacerbate many infectious diseases and, conversely, iron withholding is an important defense strategy for mammalian hosts. The mechanisms by which fungal pathogens sense iron in the mammalian host environment are poorly understood. The AIDS-associated pathogen Cryptococcus neoformans provides a unique opportunity to explore iron sensing in the context of infection because iron levels control elaboration of the polysaccharide capsule that is the major virulence factor of the fungus. Additionally, excess iron exacerbates experimental cryptococcosis. We identified the iron-responsive transcription factor Cir1 that regulates iron acquisition in C. neoformans and discovered that Cir1 also controls the expression of all of the known major virulence factors of the fungus. In particular, cir1 mutants are defective in capsule formation and avirulent in a mouse model of cryptococcosis. Thus the ability to sense iron is critical during infection by C. neoformans and may represent a target for antifungal therapy. Keywords: wt/mutant x low/high iron

2006-09-14 | GSE5341 | GEO

The ER protein translocation channel subunit Sbh1 controls virulence of Cryptococcus neoformans

Project description:C. neoformans is an opportunistic human pathogen whose polysaccharide capsule anchored to the cell wall is critical for virulence. Biogenesis of both cell wall and capsule relies on the secretory pathway. Protein secretion begins with protein translocation across the endoplasmic reticulum (ER) membrane through a highly conserved channel formed by three proteins, Sec61, Sbh1, and Sss1. Sbh1 is most divergent and contains multiple phosphorylation sites which may allow it to control entry into the secretory pathway in a regulated, species- and protein-specific manner. We show here that in contrast to S. cerevisiae, C. neoformans lacking SBH1 are barely temperature-sensitive, but that absence of SBH1 causes a cell-wall defect in both species. Comparison of the proteomes of wildtype and Δsbh1 C. neoformans revealed a small set of secretory and transmembrane proteins whose expression under infection-like conditions was upregulated in wildtype, but not in the Δsbh1 mutant. These proteins are mostly involved in cell-wall biogenesis. We found that adhesion to macrophages was compromised in the Δsbh1 strain and in mice, the C. neoformans Δsbh1 mutant was virtually avirulent. We conclude that upon contact with the host Sbh1 controls entry of virulencefactors into the secretory pathway of Cryptococcus neoformans.

2023-01-27 | PXD013894 | Pride

Zinc-associated proteome of Cryptococcus neoformans

Project description:Fungal diseases are critical burdens on the global healthcare system, infecting over 25% of the world’s population. For the opportunistic fungal pathogen, Cryptococcus neoformans, infection leads to cryptococcosis; a disease enabled by elaboration of sophisticated virulence factors, including polysaccharide capsule, melanin, thermotolerance, and extracellular enzymes in the presence of the host. Conversely, the host protects itself from fungal invasion by regulating and sequestering transition metals (e.g., iron, zinc, copper) important for microbial growth and survival. Building upon knowledge of zinc transport regulation at the transcriptional level, here, we explore the intricate relationship between zinc availability and fungal virulence via mass spectrometry-based quantitative proteomics. We observe distinct protein-level responses to zinc-limited and -excess conditions through a shift of the proteome profile towards stress response and metal acquisition, including the upregulation of the zinc transporter, ZIP1. In addition, we reveal a novel connection among zinc availability, protein folding, capsule production, and virulence through the detection of a Wos2-like ortholog in the secretome under replete conditions. Overall, we provide new biological insight into cellular remodeling at the protein level of C. neoformans under regulated zinc conditions and uncover a novel connection between zinc availability and fungal virulence. These findings support the development of new antifungal strategies focused on the enhancement of nutritional immunity within the host.

2022-02-16 | PXD023204 | Pride

Cross talk between the cell wall integrity and cAMP/protein kinase A pathways in Cryptococcus neoformans

Project description:Cryptococcus neoformans is a fungal pathogen of immunocompromised people that causes fatal meningitis. The fungal cell wall is essential to viability and pathogenesis of C. neoformans, and biosynthesis and repair of the wall is primarily controlled by the cell wall integrity (CWI) signaling pathway. Previous work by us and others have shown that deletion of genes encoding the four major kinases in the CWI signaling pathway, namely PKC1, BCK1, MKK2 and MPK1 results in severe cell wall phenotypes, sensitivity to a variety of cell wall stressors and, for Mpk1, reduced virulence in a mouse model. Here, we examined the global transcriptional response of gene deletions of BCK1, MKK2 and MPK1 compared to wild-type cells. We found over 1000 genes were differentially expressed in one or more of the deletion strains, with 115 genes differentially expressed in all three strains, many of which have been identified as genes regulated by the cAMP/protein kinase A (PKA) pathway. Biochemical measurements of cAMP levels in the kinase deletion stains revealed significantly less cAMP in all of the deletion strains compared to wild-type cells. The deletion strains also produced significantly smaller capsules than wild type KN99 under capsule inducing conditions, although they shed similar levels of capsule as wild type. Finally, addition of exogenous cAMP led to reduced sensitivity to cell wall stress and restored surface capsule to near wild-type levels. Thus, we have direct evidence of cross talk between the CWI and cAMP/PKA pathways that may have important implications for regulation of cell wall and capsule homeostasis. Comparison of three gene deletion strains to wild-type, with 3 biological replicates for each sample.

2014-07-01 | E-GEOD-57217 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data