Pleiotropic Effects of Deubiquitinating Enzymes on Growth and Pathogenesis of Cryptococcus neoformans
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ABSTRACT:
ORGANISM(S): Cryptococcus neoformans var. grubii H99 Cryptococcus neoformans Cryptococcus neoformans var. neoformans
PROVIDER: GSE36184 | GEO | 2012/04/11
SECONDARY ACCESSION(S): PRJNA151655
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the following subset Series: GSE35067: Transcriptional changes due to UBP5 mutation under temperature stress GSE36181: Transcript response of CSF survival mutants in CSF or serum GSE36182: Comparison of transcription profiles for C. neoformans during rabbit infection GSE36183: Comparison of transcription profiles of C. neoformans during rabbit or human infection Refer to individual Series
2012-04-10 | E-GEOD-36184 | biostudies-arrayexpress
Project description:Ubiquitination is a reversible protein modification that influences various cellular processes in eukaryotic cells. Deubiquitinating enzymes remove ubiquitin, maintain ubiquitin homeostasis and regulate protein degradation via the ubiquitination pathway. Cryptococcus neoformans is an important basidiomycete pathogen that causes life-threatening meningoencephalitis primarily in the immunocompromised population. In order to understand the possible influence deubiquitinases have on growth and virulence of the model pathogenic yeast Cryptococcus neoformans, we generated deletion mutants of seven putative deubiquitinase genes. Compared to other deubiquitinating enzyme mutants, a ubp5Δ mutant exhibited severely attenuated virulence and many distinct phenotypes, including decreased capsule formation, hypomelanization, defective sporulation, and elevated sensitivity to several external stressors (such as high temperature, oxidative and nitrosative stresses, high salts, and antifungal agents). Ubp5 is likely the major deubiquitinating enzyme for stress responses in C. neoformans, which further delineates the evolutionary divergence of Cryptococcus from the model yeast S. cerevisiae, and provides an important paradigm for understanding the potential role of deubiquitination in virulence by other pathogenic fungi. Other putative deubiquitinase mutants (doa4Δ and ubp13Δ) share some phenotypes with the ubp5Δ mutant, illustrating functional overlap among deubiquitinating enzymes in C. neoformans. Therefore, deubiquitinating enzymes (especially Ubp5) are essential for the virulence composite of C. neoformans and provide an additional yeast survival and propagation advantage in the host.
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Project description:The manifestation of virulence traits in Cryptococcus neoformans is thought to rely on intracellular transport, a process not fully explored in this pathogenic fungus. Through interaction cloning, we identified a multi-modular protein, Cin1 (cryptococcal intersectin 1), whose domain structure is similar to that of the human endocytic protein ITSN1. Cin1 contains an N-terminal EH domain, a central coiled-coil region, a WH2 domain, two SH3 domains and a C-terminal RhoGEF (DH)-PH domain. Interestingly, alternative mRNA splicing resulted in two Cin1 isoforms, and Cin1 homologues are also restricted to basidiomycetous fungi. Disruption of the CIN1 gene had a pleiotropic effect on growth, normal cytokinesis, intracellular transports and the production of several virulence factors. Additionally, Cin1 interacts with cryptococcal Cdc42 and Wsp1 (a WASP homologue) proteins in vitro, suggesting a conserved role in the regulation of the actin cytoskeleton. However, deletion of RhoGEF or SH3 and RhoGEF domains did not result in any phenotypic changes, suggesting that functional redundancy exists in proteins containing similar domains or that the activities by other domains are necessary for Cin1 function. Our study presents the first evidence of a multi-modular protein whose function in intracellular transport underlies the growth, differentiation and virulence of a pathogenic microorganism.
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Project description:Msi1-like (MSIL) proteins contain WD40 motifs and have a pleiotropic cellular function as negative regulators of the Ras/cyclic AMP (cAMP) pathway and components of chromatin assembly factor 1 (CAF-1), yet they have not been studied in fungal pathogens. Here we identified and characterized an MSIL protein, Msl1, in Cryptococcus neoformans, which causes life-threatening meningoencephalitis in humans. Notably, Msl1 plays pleiotropic roles in C. neoformans in both cAMP-dependent and -independent manners largely independent of Ras. Msl1 negatively controls antioxidant melanin production and sexual differentiation, and this was repressed by the inhibition of the cAMP-signaling pathway. In contrast, Msl1 controls thermotolerance, diverse stress responses, and antifungal drug resistance in a Ras/cAMP-independent manner. Cac2, which is the second CAF-1 component, appears to play both redundant and distinct functions compared to the functions of Msl1. Msl1 is required for the full virulence of C. neoformans. Transcriptome analysis identified a group of Msl1-regulated genes, which include stress-related genes such as HSP12 and HSP78. In conclusion, this study demonstrates pleiotropic roles of Msl1 in the human fungal pathogen C. neoformans, providing insight into a potential novel antifungal therapeutic target.
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Project description:Metastatic melanoma is the leading cause of death from skin cancer. Therapies targeting the BRAF oncogenic pathway and immunotherapies show remarkable clinical efficacy. However, these treatments are limited to subgroups of patients and relapse is common. Overall, the majority of patients require additional treatments, justifying the development of new therapeutic strategies. Non-genetic and genetic alterations are considered to be important drivers of cellular adaptation mechanisms to current therapies and disease relapse. Importantly, modification of the overall proteome in response to non-genetic and genetic events supports major cellular changes that are required for the survival, proliferation, and migration of melanoma cells. However, the mechanisms underlying these adaptive responses remain to be investigated. The major contributor to proteome remodeling involves the ubiquitin pathway, ubiquitinating enzymes, and ubiquitin-specific proteases also known as DeUBiquitinases (DUBs). In this review, we summarize the current knowledge regarding the nature and roles of the DUBs recently identified in melanoma progression and therapeutic resistance and discuss their potential as novel sources of vulnerability for melanoma therapy.
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Project description:The target of rapamycin (TOR) pathway is an evolutionarily conserved signal transduction system that governs a plethora of eukaryotic biological processes, but its role in Cryptococcus neoformans remains elusive. In this study, we investigated the TOR pathway by functionally characterizing two Tor-like kinases, Tor1 and Tlk1, in C. neoformans We successfully deleted TLK1, but not TOR1TLK1 deletion did not result in any evident in vitro phenotypes, suggesting that Tlk1 is dispensable for the growth of C. neoformans We demonstrated that Tor1, but not Tlk1, is essential and the target of rapamycin by constructing and analyzing conditionally regulated strains and sporulation analysis of heterozygous mutants in the diploid strain background. To further analyze the Tor1 function, we constructed constitutive TOR1 overexpression strains. Tor1 negatively regulated thermotolerance and the DNA damage response, which are two important virulence factors of C. neoformansTOR1 overexpression reduced Mpk1 phosphorylation, which is required for cell wall integrity and thermoresistance, and Rad53 phosphorylation, which governs the DNA damage response pathway. Tor1 is localized to the cytoplasm, but enriched in the vacuole membrane. Phosphoproteomics and transcriptomics revealed that Tor1 regulates a variety of biological processes, including metabolic processes, cytoskeleton organization, ribosome biogenesis, and stress response. TOR inhibition by rapamycin caused actin depolarization in a Tor1-dependent manner. Finally, screening rapamycin-sensitive and -resistant kinase and transcription factor mutants revealed that the TOR pathway may crosstalk with a number of stress signaling pathways. In conclusion, our study demonstrates that a single Tor1 kinase plays pleiotropic roles in C. neoformans.
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Project description:Cryptococcus neoformans is a major human pathogen and a cause of meningoencephalitis in immunocompromised patients. Many factors contribute to the extraordinary survivability and pathogenicity of this fungus in humans, including copper homeostasis pathways. Previous work has shown that deletion of the copper-dependent regulator Cuf1 results in decreased virulence and dissemination in brain infection, suggesting that copper acquisition is important to the persistence of this pathogen. Here, we show that the minimal copper quota of C. neoformans is maintained at a high level even when grown under conditions of stringent copper limitation. Intriguingly, when this fungal pathogen is grown in standard and copper-enriched media, it sequesters even higher levels of this essential metal, achieving levels that are far higher than non-pathogenic S. cerevisiae. The hypothesis that copper acquisition plays an essential role in virulence is further corroborated by the findings that a hypovirulent CUF1-deletant strain of C. neoformans retrieved from infected mice contains almost a 6-fold lower concentration of intracellular copper than the pathogenic wild-type strain. The concentration difference arises in part from larger-sized cuf1? cell. Under in vitro growth conditions, the size of the cuf1? cells is normal and the hypertrophy phenotype is readily induced in vitro under conditions of copper starvation. Taken together, these data suggest that acquisition of extraordinary levels of copper is an important factor in the survivability of the pathogen in the copper-deplete environment of infection, and effective copper concentration may play an important role in the pathogenesis of C. neoformans.
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