The protein secretory pathway of <i>Candida albicans</i>

Fonzi, William A.

doi:10.1111/j.1439-0507.2008.01673.x

Cited by 23 publications

(29 citation statements)

References 118 publications

(245 reference statements)

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“…The exact C. albicans factors triggering macrophage pyroptosis are currently unknown, yet recent investigations revealed that the level of hyphal formation and exposure of specific moieties on the fungal cell wall play a role in this process (14)(15)(16). Since neutral pH is a potent morphogenetic signal in C. albicans and cell wall composition depends on the available carbon sources (25,26), we explored if the effects of the stp2Δ and ahr1Δ mutations on IL-1␤ release were related to the inability of the mutants to prevent phagosomal acidification. For this purpose, we pretreated the J774A.1 macrophages with the vATPase inhibitor BafA to generate neutral phagosomes, followed by addition of C. albicans strains.…”

Section: Resultsmentioning

confidence: 99%

Phagosomal Neutralization by the Fungal Pathogen Candida albicans Induces Macrophage Pyroptosis

Vylkova

Lorenz

2017

Infect Immun

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The interaction of Candida albicans with the innate immune system is the key determinant of the pathogen/commensal balance and has selected for adaptations that facilitate the utilization of nutrients commonly found within the host, including proteins and amino acids; many of the catabolic pathways needed to assimilate these compounds are required for persistence in the host. We have shown that C. albicans co-opts amino acid catabolism to generate and excrete ammonia, which raises the extracellular pH, both in vitro and in vivo and induces hyphal morphogenesis. Mutants defective in the uptake or utilization of amino acids, such as those lacking STP2, a transcription factor that regulates the expression of amino acid permeases, are impaired in multiple aspects of fungus-macrophage interactions resulting from an inability to neutralize the phagosome. Here we identified a novel role in amino acid utilization for Ahr1p, a transcription factor previously implicated in regulation of adherence and hyphal morphogenesis. Mutants lacking AHR1 were defective in growth, alkalinization, and ammonia release on amino acid-rich media, similar to stp2Δ and ahr1Δ stp2Δ cells, and occupied more acidic phagosomes. Notably, ahr1Δ and stp2Δ strains did not induce pyroptosis, as measured by caspase-1-dependent interleukin-1␤ release, though this phenotype could be suppressed by pharmacological neutralization of the phagosome. Altogether, we show that C. albicans-driven neutralization of the phagosome promotes hyphal morphogenesis, sufficient for induction of caspase-1-mediated macrophage lysis.

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Section: Resultsmentioning

confidence: 99%

Phagosomal Neutralization by the Fungal Pathogen Candida albicans Induces Macrophage Pyroptosis

Vylkova

Lorenz

2017

Infect Immun

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“…Despite the fact that the transition from the a virulent form of C. albicans to a pathogenic one requires the secretion of proteins to the cell surface and surrounding matrix, few studies have investigated the basic biology of the early secretory pathway in C. albicans , namely the translocation of secretory proteins into the endoplasmic reticulum (ER; reviewed in Fonzi 2009). A few C. albicans proteins presumed to play roles in the early secretory pathway have been shown to function similarly to their Saccharomyces cerevisiae orthologs, such as SEC65 (Regnacq et al 1998) and SPC3 , an ER resident protein involved in N-terminal signal sequence cleavage (De la Rosa et al 2004a).…”

Section: Introductionmentioning

confidence: 99%

The Candida albicans Kar2 protein is essential and functions during the translocation of proteins into the endoplasmic reticulum

et al. 2010

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Since the secretory pathway is essential for Candida albicans to transition from a commensal organism to a pathogen, an understanding of how this pathway functions may be beneficial for identifying novel drug targets to prevent candidiasis. We have cloned the C. albicans KAR2 gene, which performs many roles during the translocation of proteins into the endoplasmic reticulum (ER) during the first committed step of the secretory pathway in many eukaryotes. Our results show that C. albicans KAR2 is essential, and that the encoded protein rescues a temperature-sensitive growth defect found in a Saccharomyces cerevisiae strain harboring a mutant form of the Kar2 protein. Additionally, S. cerevisiae containing CaKAR2 as the sole copy of this essential gene are viable, and ER microsomes prepared from this strain exhibit wild-type levels of post-translational translocation during in vitro translocation assays. Finally, ER microsomes isolated from a C. albicans strain expressing reduced amounts of KAR2 mRNA are defective for in vitro translocation of a secreted substrate protein, establishing a new method to study ER translocation in this organism. Together, these results suggest that C. albicans Kar2p functions during the translocation of proteins into the ER during the first step of the secretory pathway.

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“…These secreted proteases are required for pathogenicity, as they take part in fungal attachment, invasion, and subsequent tissue damage (4)(5)(6)(7). These factors are secreted by mechanisms that include traditional signal peptide-based secretion using systems homologous to those in the model yeast Saccharomyces cerevisiae as well as nontraditional secretion (8,9).…”

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confidence: 99%

Lipid Biosynthetic Genes Affect Candida albicans Extracellular Vesicle Morphology, Cargo, and Immunostimulatory Properties

et al. 2015

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dMicrobial secretion is integral for regulating cell homeostasis as well as releasing virulence factors during infection. The genes encoding phosphatidylserine synthase (CHO1) and phosphatidylserine decarboxylase (PSD1 and PSD2) are Candida albicans genes involved in phospholipid biosynthesis, and mutations in these genes affect mitochondrial function, cell wall thickness, and virulence in mice. We tested the roles of these genes in several agar-based secretion assays and observed that the cho1⌬/⌬ and psd1⌬/⌬ psd2⌬/⌬ strains manifested less protease and phospholipase activity. Since extracellular vesicles (EVs) are surrounded by a lipid membrane, we investigated the effects of these mutations on EV structure, composition, and biological activity. The cho1⌬/⌬ mutant releases EVs comparable in size to wild-type EVs, but EVs from the psd1⌬/⌬ psd2⌬/⌬ strain are much larger than those from the wild type, including a population of >100-nm EVs not observed in the EVs from the wild type. Proteomic analysis revealed that EVs from both mutants had a significantly different protein cargo than that of EVs from the wild type. EVs were tested for their ability to activate NF-B in bone marrow-derived macrophage cells. While wild-type and psd1⌬/⌬ psd2⌬/⌬ mutant-derived EVs activated NF-B, the cho1⌬/⌬ mutant-derived EV did not. These studies indicate that the presence and absence of these C. albicans genes have qualitative and quantitative effects on EV size, composition, and immunostimulatory phenotypes that highlight a complex interplay between lipid metabolism and vesicle production.

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The protein secretory pathway of Candida albicans

Cited by 23 publications

References 118 publications

Phagosomal Neutralization by the Fungal Pathogen Candida albicans Induces Macrophage Pyroptosis

Phagosomal Neutralization by the Fungal Pathogen Candida albicans Induces Macrophage Pyroptosis

The Candida albicans Kar2 protein is essential and functions during the translocation of proteins into the endoplasmic reticulum

Lipid Biosynthetic Genes Affect Candida albicans Extracellular Vesicle Morphology, Cargo, and Immunostimulatory Properties

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