scholarly journals Conserved Elements of the RAM Signaling Pathway Establish Cell Polarity in the BasidiomyceteCryptococcus neoformansin a Divergent Fashion from Other Fungi

2006 ◽  
Vol 17 (9) ◽  
pp. 3768-3780 ◽  
Author(s):  
Felicia J. Walton ◽  
Joseph Heitman ◽  
Alexander Idnurm
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Insertional Mutagenesis ◽  
Pathogenic Fungus ◽  
Cell Polarization ◽  
Targeted Deletion ◽  
Complex Processes ◽  
Capsule Production ◽  
Human Pathogenic Fungus ◽  
Differentiation And Proliferation

In eukaryotes the complex processes of development, differentiation, and proliferation require carefully orchestrated changes in cellular morphology. Single-celled eukaryotes provide tractable models for the elucidation of signaling pathways involved in morphogenesis. Here we describe a pathway regulating cell polarization and separation in the human pathogenic fungus Cryptococcus neoformans. An insertional mutagenesis screen identified roles for the ARF1, CAP60, NDH1, KIC1, CBK1, SOG2, and TAO3 genes in establishing normal colony morphology. ARF1 and CAP60 are also required for capsule production, a virulence factor, and ARF1 confers resistance to the antifungal fluconazole. KIC1, CBK1, SOG2, and TAO3 are homologues of genes conserved in other eukaryotes; in Saccharomyces cerevisiae they constitute components of the RAM (regulation of Ace2p activity and cellular morphogenesis) signaling pathway. A targeted deletion of a fifth component of RAM (MOB2) conferred identical phenotypes to kic1, cbk1, sog2, or tao3 mutations. Characterization of these genes in C. neoformans revealed unique features of the RAM pathway in this organism. Loss of any of these genes caused constitutive hyperpolarization instead of the loss of polarity seen in S. cerevisiae. Furthermore, sensitivity to the drugs FK506 and cyclosporin A demonstrates that the RAM pathway acts in parallel with the protein phosphatase calcineurin in C. neoformans but not in S. cerevisiae. These results indicate that conserved signaling pathways serve both similar and divergent cellular roles in morphogenesis in these divergent organisms.

scholarly journals The CDC42 Homolog of the Dimorphic FungusPenicillium marneffei Is Required for Correct Cell Polarization during Growth but Not Development

2001 ◽  
Vol 183 (11) ◽  
pp. 3447-3457 ◽  
Author(s):  
Kylie J. Boyce ◽  
Michael J. Hynes ◽  
Alex Andrianopoulos
Keyword(s):  
Cell Shape ◽  
Pathogenic Fungus ◽  
Cell Polarization ◽  
Dominant Negative ◽  
Yeast Cells ◽  
Polarized Growth ◽  
Temperature Dependent ◽  
Human Pathogenic Fungus ◽  
Rho Family

ABSTRACT The opportunistic human pathogenic fungus Penicillium marneffei is dimorphic and is thereby capable of growth either as filamentous multinucleate hyphae or as uninucleate yeast cells which divide by fission. The dimorphic switch is temperature dependent and requires regulated changes in morphology and cell shape. Cdc42p is a Rho family GTPase which in Saccharomyces cerevisiae is required for changes in polarized growth during mating and pseudohyphal development. Cdc42p homologs in higher organisms are also associated with changes in cell shape and polarity. We have cloned a highly conserved CDC42 homolog from P. marneffeinamed cflA. By the generation of dominant-negative and dominant-activated cflA transformants, we have shown that CflA initiates polarized growth and extension of the germ tube and subsequently maintains polarized growth in the vegetative mycelium. CflA is also required for polarization and determination of correct cell shape during yeast-like growth, and active CflA is required for the separation of yeast cells. However, correct cflAfunction is not required for dimorphic switching and does not appear to play a role during the generation of specialized structures during asexual development. In contrast, heterologous expression ofcflA alleles in Aspergillus nidulansprevented conidiation.

scholarly journals Heterotrimeric G-Protein Signalers and RGSs in Aspergillus fumigatus

Pathogens ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 902
Author(s):  
Hee-Soo Park ◽  
Min-Ju Kim ◽  
Jae-Hyuk Yu ◽  
Kwang-Soo Shin
Keyword(s):  
Aspergillus Fumigatus ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
G Protein ◽  
G Proteins ◽  
Pathogenic Fungus ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Heterotrimeric G Protein ◽  
External Signals

The heterotrimeric G-protein (G-protein) signaling pathway is one of the most important signaling pathways that transmit external signals into the inside of the cell, triggering appropriate biological responses. The external signals are sensed by various G-protein-coupled receptors (GPCRs) and transmitted into G-proteins consisting of the α, β, and γ subunits. Regulators of G-protein signaling (RGSs) are the key controllers of G-protein signaling pathways. GPCRs, G-proteins, and RGSs are the primary upstream components of the G-protein signaling pathway, and they are highly conserved in most filamentous fungi, playing diverse roles in biological processes. Recent studies characterized the G-protein signaling components in the opportunistic pathogenic fungus Aspergillus fumigatus. In this review, we have summarized the characteristics and functions of GPCRs, G-proteins, and RGSs, and their regulatory roles in governing fungal growth, asexual development, germination, stress tolerance, and virulence in A. fumigatus.

scholarly journals Peroxisomal and Mitochondrial β-Oxidation Pathways Influence the Virulence of the Pathogenic Fungus Cryptococcus neoformans

2012 ◽  
Vol 11 (8) ◽  
pp. 1042-1054 ◽  
Author(s):  
Matthias Kretschmer ◽  
Joyce Wang ◽  
James W. Kronstad
Keyword(s):  
Carbon Source ◽  
Cryptococcus Neoformans ◽  
Virulence Factor ◽  
Fungal Pathogens ◽  
Pathogenic Fungus ◽  
Subsequent Work ◽  
Content Type ◽  
Capsule Production ◽  
Human Pathogenic Fungus ◽  
Host Tissues

ABSTRACTAn understanding of the connections between metabolism and elaboration of virulence factors during host colonization by the human-pathogenic fungusCryptococcus neoformansis important for developing antifungal therapies. Lipids are abundant in host tissues, and fungal pathogens in the phylum basidiomycota possess both peroxisomal and mitochondrial β-oxidation pathways to utilize this potential carbon source. In addition, lipids are important signaling molecules in both fungi and mammals. In this report, we demonstrate that defects in the peroxisomal and mitochondrial β-oxidation pathways influence the growth ofC. neoformanson fatty acids as well as the virulence of the fungus in a mouse inhalation model of cryptococcosis. Disease attenuation may be due to the cumulative influence of altered carbon source acquisition or processing, interference with secretion, changes in cell wall integrity, and an observed defect in capsule production for the peroxisomal mutant. Altered capsule elaboration in the context of a β-oxidation defect was unexpected but is particularly important because this trait is a major virulence factor forC. neoformans. Additionally, analysis of mutants in the peroxisomal pathway revealed a growth-promoting activity forC. neoformans, and subsequent work identified oleic acid and biotin as candidates for such factors. Overall, this study reveals that β-oxidation influences virulence inC. neoformansby multiple mechanisms that likely include contributions to carbon source acquisition and virulence factor elaboration.

scholarly journals Identification of ENA1 as a Virulence Gene of the Human Pathogenic Fungus Cryptococcus neoformans through Signature-Tagged Insertional Mutagenesis

2009 ◽  
Vol 8 (3) ◽  
pp. 315-326 ◽  
Author(s):  
Alexander Idnurm ◽  
Felicia J. Walton ◽  
Anna Floyd ◽  
Jennifer L. Reedy ◽  
Joseph Heitman
Keyword(s):  
Cryptococcus Neoformans ◽  
Fungal Pathogens ◽  
Insertional Mutagenesis ◽  
Pathogenic Fungus ◽  
Mammalian Host ◽  
New Genes ◽  
Strain Collection ◽  
Mutant Strains ◽  
Human Pathogenic Fungus

ABSTRACT A library of more than 4,500 signature-tagged insertion mutants of the human pathogenic fungus Cryptococcus neoformans was generated, and a subset was screened in a murine inhalation model to identify genes required for virulence. New genes that regulate aspects of C. neoformans virulence were also identified by screening the entire library for in vitro phenotypes related to the ability to cause disease, including melanin production, growth at high temperature, and growth under conditions of nutrient limitation. A screen of 10% of the strain collection in mice identified an avirulent mutant strain with an insertion in the ENA1 gene, which is predicted to encode a fungus-specific sodium or potassium P-type ATPase. The results of the deletion of the gene and complementation experiments confirmed its key role in mammalian virulence. ena1 mutant strains exhibited no change in sensitivity to high salt concentrations but were sensitive to alkaline pH conditions, providing evidence that the fungus may have to survive at elevated pH during infection of the mammalian host. The mutation of the well-characterized virulence factor calcineurin (CNA1) also rendered C. neoformans strains sensitive to elevated pH. ENA1 transcripts in wild-type and cna1 mutant strains were upregulated in response to high pH, and cna1 ena1 double mutant strains exhibited increased sensitivity to elevated pH, indicating that at least two pathways in the fungus mediate survival under alkaline conditions. Signature-tagged mutagenesis is an effective strategy for the discovery of new virulence genes in fungal pathogens of animals.

Thioridazine inhibits gene expression control of the cell wall signaling pathway (CWI) in the human pathogenic fungus Paracoccidioides brasiliensis

2016 ◽  
Vol 291 (3) ◽  
pp. 1347-1362 ◽  
Author(s):  
Daniela Leite Jabes ◽  
Ana Claudia de Freitas Oliveira ◽  
Valquíria Campos Alencar ◽  
Fabiano Bezerra Menegidio ◽  
Débora Liliane Souza Reno ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Wall ◽  
Signaling Pathway ◽  
Paracoccidioides Brasiliensis ◽  
Pathogenic Fungus ◽  
Expression Control ◽  
Gene Expression Control ◽  
Human Pathogenic Fungus

scholarly journals Plasma Membrane Organization Is Essential for Balancing Competing Pseudopod- and Uropod-promoting Signals during Neutrophil Polarization and Migration

2005 ◽  
Vol 16 (12) ◽  
pp. 5773-5783 ◽  
Author(s):  
Stéphane Bodin ◽  
Matthew D. Welch
Keyword(s):  
Plasma Membrane ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Cell Polarization ◽  
Cholesterol Depletion ◽  
Membrane Organization ◽  
And Migration ◽  
Outstanding Question ◽  
Cytoskeletal Elements ◽  
Rhoa Signaling

Exposure of neutrophils to chemoattractant induces cell polarization and migration. These behaviors require the asymmetric activation of distinct signaling pathways and cytoskeletal elements in the protruding pseudopod at the front of cells and the retracting uropod at the rear. An important outstanding question is, how does the organization of the plasma membrane participate in establishing asymmetry during polarization and migration? To answer this question, we investigated the function of cholesterol, a lipid known to influence membrane organization. Using controlled cholesterol depletion, we found that a cholesterol-dependent membrane organization enabled cell polarization and migration by promoting uropod function and suppressing ectopic pseudopod formation. At a mechanistic level, we showed that cholesterol was directly required for suppressing inappropriate activation of the pseudopod-promoting Gi/PI3-kinase signaling pathway. Furthermore, cholesterol was required for dampening Gi-dependent negative feedback on the RhoA signaling pathway, thus enabling RhoA activation and uropod function. Our findings suggest a model in which a cholesterol-dependent membrane organization plays an essential role in the establishment of cellular asymmetry by balancing the activation and segregating the localization of competing pseudopod- and uropod-inducing signaling pathways during neutrophil polarization and migration.

Targeted Delivery of Natural Bioactives and Lipid-nanocargos against Signaling Pathways Involved in Skin Cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Mohammad Kashif Iqubal ◽  
Aiswarya Chaudhuri ◽  
Ashif Iqubal ◽  
Sadaf Saleem ◽  
Madan Mohan Gupta ◽  
...  
Keyword(s):  
Skin Cancer ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Targeted Delivery ◽  
Skin Pigmentation ◽  
Wnt Signaling Pathway ◽  
Human Beings ◽  
Radiation Chemical ◽  
Cell Leukemia Virus Type ◽  
Human T Cell

: At present, skin cancer is a widespread malignancy in human beings. Among diverse population types, Caucasian populations are much more prone in comparison to darker skin populations due to the comparative lack of skin pigmentation. Skin cancer is divided into malignant and non-melanoma skin cancer, which is additionally categorized as basal and squamous cell carcinoma. The exposure to ultraviolet radiation, chemical carcinogen (polycyclic aromatic hydrocarbons, arsenic, tar, etc.), and viruses (herpes virus, human papillomavirus, and human T-cell leukemia virus type-1) are major contributing factors of skin cancer. There are distinct pathways available through which skin cancer develops, such as the JAKSTAT pathway, Akt pathway, MAPKs signaling pathway, Wnt signaling pathway, to name a few. Currently, several targeted treatments are available, such as monoclonal antibodies, which have dramatically changed the line of treatment of this disease but possess major therapeutic limitations. Thus, recently many phytochemicals have been evaluated either alone or in combination with the existing synthetic drugs to overcome their limitations and have found to play a promising role in the prevention and treatment. In this review, complete tracery of skin cancer, starting from the signaling pathways involved, newer developed drugs with their targets and limitations along with the emerging role of natural products alone or in combination as potent anticancer agents and their molecular mechanism involved has been discussed. Apart from this, various nanocargos have also been mentioned here, which can play a significant role in the management and treatment of different types of skin cancer.

Biological role of AKT, and regulation of AKT signaling pathway by thymoquinone: perspectives in cancer therapeutics

2020 ◽  
Vol 20 ◽  
Author(s):  
Md. Junaid ◽  
Yeasmin Akter ◽  
Syeda Samira Afrose ◽  
Mousumi Tania ◽  
Md. Asaduzzaman Khan
Keyword(s):  
Clinical Trials ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Inhibitory Effect ◽  
Akt Signaling ◽  
Review Article ◽  
Therapeutic Drug ◽  
Akt Signaling Pathway ◽  
Anti Cancer

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to the carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. Objective: In this review article, we have interpreted the role of AKT signaling pathways in cancer and natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanism. Method: We have collected the updated information and data on AKT, their role in cancer and inhibitory effect of TQ in AKT signaling pathway from google scholar, PubMed, Web of Science, Elsevier, Scopus and many more. Results: There are many drugs already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

scholarly journals Expression Patterns in Reductive Iron Assimilation and Functional Consequences during Phagocytosis of Lichtheimia corymbifera, an Emerging Cause of Mucormycosis

2021 ◽  
Vol 7 (4) ◽  
pp. 272
Author(s):  
Felicia Adelina Stanford ◽  
Nina Matthias ◽  
Zoltán Cseresnyés ◽  
Marc Thilo Figge ◽  
Mohamed I. Abdelwahab Hassan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Iron Uptake ◽  
Intracellular Transport ◽  
Pathogenic Fungus ◽  
Expression Patterns ◽  
Iron Depletion ◽  
Iron Assimilation ◽  
Human Pathogenic Fungus ◽  
Hyphal Formation ◽  
Yeast Mutants

Iron is an essential micronutrient for most organisms and fungi are no exception. Iron uptake by fungi is facilitated by receptor-mediated internalization of siderophores, heme and reductive iron assimilation (RIA). The RIA employs three protein groups: (i) the ferric reductases (Fre5 proteins), (ii) the multicopper ferroxidases (Fet3) and (iii) the high-affinity iron permeases (Ftr1). Phenotyping under different iron concentrations revealed detrimental effects on spore swelling and hyphal formation under iron depletion, but yeast-like morphology under iron excess. Since access to iron is limited during pathogenesis, pathogens are placed under stress due to nutrient limitations. To combat this, gene duplication and differential gene expression of key iron uptake genes are utilized to acquire iron against the deleterious effects of iron depletion. In the genome of the human pathogenic fungus L. corymbifera, three, four and three copies were identified for FRE5, FTR1 and FET3 genes, respectively. As in other fungi, FET3 and FTR1 are syntenic and co-expressed in L. corymbifera. Expression of FRE5, FTR1 and FET3 genes is highly up-regulated during iron limitation (Fe-), but lower during iron excess (Fe+). Fe- dependent upregulation of gene expression takes place in LcFRE5 II and III, LcFTR1 I and II, as well as LcFET3 I and II suggesting a functional role in pathogenesis. The syntenic LcFTR1 I–LcFET3 I gene pair is co-expressed during germination, whereas LcFTR1 II- LcFET3 II is co-expressed during hyphal proliferation. LcFTR1 I, II and IV were overexpressed in Saccharomyces cerevisiae to represent high and moderate expression of intracellular transport of Fe3+, respectively. Challenge of macrophages with the yeast mutants revealed no obvious role for LcFTR1 I, but possible functions of LcFTR1 II and IVs in recognition by macrophages. RIA expression pattern was used for a new model of interaction between L. corymbifera and macrophages.

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