Brefeldin A blocks an early stage of protein transport in Candida albicans

Arioka, Manabu; Hirata, Aiko; Takatsuki, Akira; Yamasaki, Makari

doi:10.1099/00221287-137-6-1253

Cited by 16 publications

(6 citation statements)

References 40 publications

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“…Eukaryotic pathogens that are extracellular secrete virulence determinants to their surface via an ER-type SS (37,38). However, those that reside intracellularly need an additional vacuolar export signal to be delivered to the host cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

Cooperative domains define a unique host cell-targeting signal in Plasmodium falciparum -infected erythrocytes

López-Estraño

Bhattacharjee

Harrison

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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When the malaria parasite Plasmodium falciparum infects an erythrocyte, it resides in a parasitophorous vacuole and remarkably exports proteins into the periphery of its host cell. Two of these proteins, the histidine-rich proteins I and II (PfHRPI and PfHRPII), are exported to the erythrocyte cytoplasm. PfHRPI has been linked to cell-surface ''knobby'' protrusions that mediate cerebral malaria and are a frequent cause of death. PfHRPII has been implicated in (i) the production of hemozoin, the black pigment associated with disease, as well as (ii) interactions with the erythrocyte cytoskeleton. Here we show that a tripartite signal that is comprised of an endoplasmic reticulum-type signal sequence followed by a bipartite vacuolar translocation signal derived from HRPII and HRPI exports GFP from the parasitophorous vacuole to the host cytoplasm. The bipartite vacuolar translocation signal is comprised of unique, peptidic (Ϸ40-aa) sequences. A domain within it contains the signal for export to ''cleft'' transport intermediates in the host erythrocyte and may thereby regulate the pathway of export to the host cytoplasm. A signal for posttranslational, vacuolar exit of proteins has hitherto not been described in eukaryotic secretion.

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Section: Discussionmentioning

confidence: 99%

Cooperative domains define a unique host cell-targeting signal in Plasmodium falciparum -infected erythrocytes

López-Estraño

Bhattacharjee

Harrison

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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“…Among the cytotoxic molecules were several molecules that have known antifungal activity, such as tamoxifen (Beggs, 1993), b-lapachone (Guiraud et al, 1994), brefeldin A (Arioka et al, 1991), rapamycin (Cruz et al, 2001) and cerulenin (Hoberg et al, 1983). In addition to the protein kinase C inhibitor tamoxifen, 17 other known protein kinase or protein phosphatase inhibitors were identified as cytotoxic ( Table 1).…”

Section: Identification Of Cytotoxic Moleculesmentioning

confidence: 99%

Inhibitors of cellular signalling are cytotoxic or block the budded-to-hyphal transition in the pathogenic yeast Candida albicans

Toenjes

Stark

Brooks

et al. 2009

Journal of Medical Microbiology

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The pathogenic yeast Candida albicans can grow in multiple morphological states including budded, pseudohyphal and true hyphal forms. The ability to interconvert between budded and hyphal forms, herein termed the budded-to-hyphal transition (BHT), is important for C. albicans virulence, and is regulated by multiple environmental and cellular signals. To identify smallmolecule inhibitors of known cellular processes that can also block the BHT, a microplate-based morphological assay was used to screen the BIOMOL-Institute of Chemistry and Cell Biology (ICCB) Known Bioactives collection from the ICCB-Longwood Screening Facility (Harvard Medical School, Boston, MA, USA). Of 480 molecules tested, 53 were cytotoxic to C. albicans and 16 were able to block the BHT without inhibiting budded growth. These 16 BHT inhibitors affected protein kinases, protein phosphatases, Ras signalling pathways, G protein-coupled receptors, calcium homeostasis, nitric oxide and guanylate cyclase signalling, and apoptosis in mammalian cells. Several of these molecules were also able to inhibit filamentous growth in other Candida species, as well as the pathogenic filamentous fungus Aspergillus fumigatus, suggesting a broad fungal host range for these inhibitory molecules. Results from secondary assays, including hyphal-specific transcription and septin localization analysis, were consistent with the inhibitors affecting known BHT signalling pathways in C. albicans. Therefore, these molecules will not only be invaluable in deciphering the signalling pathways regulating the BHT, but also may serve as starting points for potential new antifungal therapeutics. INTRODUCTIONCandida albicans is a major opportunistic pathogen of immunocompromised hosts (Schmidt-Westhausen et al., 1991;Warnock, 2007), as well as a leading cause of nosocomial bloodstream infections, especially in patients with indwelling medical devices (Kojic & Darouiche, 2004;Lynch & Robertson, 2008). C. albicans can grow as either budded (yeast-like) or filamentous cells, the latter comprising pseudohyphae and true hyphae (Sudbery et al., 2004). Both budded and hyphal cells are found at sites of infection, and the ability to undergo the budded-to-hyphal transition (BHT) is important for virulence (Saville et al., 2003). C. albicans mutants that have defects in the BHT have a reduced ability to become internalized and to cause endothelial cell injury in vitro (Phan et al., 2000), and small-molecule inhibitors of the BHT can protect endothelial cells from C. albicans-induced cell damage (Toenjes et al., 2005). These data are indicative that the BHT can modulate the ability of C. albicans to cause endothelial cell injury and suggest that the BHT is critical for systemic candidiasis.The BHT occurs in response to a variety of environmental signals, including temperature above 35 u C, pH above 6.5, nutrient starvation and growth in serum (Ernst, 2000). Therefore, it is not surprising that multiple signalling pathways regulate the BHT (Biswas et al., 2007;Brown, 2002). Genetic analysis ...

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“…Interestingly, electron microscopical observation revealed that BFA caused disappearance of the Golgi apparatus in animal cells and induced aberrant membrane structures in Candida albicans (2,19). Recently it has been reported that BFA inhibits exchange of GDP for GTP bound to ADP ribosylation factor (ARF) on the Golgi membranes, resulting in perturbation of the budding process of transport vesicles (8,12).…”

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confidence: 99%

bfr1+, a novel gene of Schizosaccharomyces pombe which confers brefeldin A resistance, is structurally related to the ATP-binding cassette superfamily

et al. 1995

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We have isolated a Schizosaccharomyces pombe gene, bfr1 ؉ , which on a multicopy plasmid vector, pDB248, confers resistance to brefeldin A (BFA), an inhibitor of intracellular protein transport. This gene encodes a novel protein of 1,531 amino acids with an intramolecular duplicated structure, each half containing a single ATP-binding consensus sequence and a set of six transmembrane sequences. This structural characteristic of bfr1 ؉ protein resembles that of mammalian P-glycoprotein, which, by exporting a variety of anticancer drugs, has been shown to be responsible for multidrug resistance in tumor cells. Consistent with this is that S. pombe cells harboring bfr1 Living organisms can export and import a variety of molecules across the plasma membrane. For this purpose, they have evolved specialized membrane-associated transport systems, one of which is mediated by transport proteins belonging to the ATP-binding cassette (ABC) superfamily (1, 13). The ABC superfamily consists of transporters which typically have four functional domains, two of which are hydrophobic and have several membrane-spanning sequences while the other two domains are hydrophilic and have highly conserved ATP-binding sequences that couple ATP hydrolysis to transport processes. In procaryotes the ATP-binding and transmembrane domains are frequently expressed as separate polypeptides, while in eucaryotic ABC transporters they are fused to larger proteins. A well-known example of the latter is multidrugresistance-conferring P-glycoprotein, which, by exporting a variety of anticancer drugs from the cells, is involved in pleiotropic drug resistance in tumor cells (10). P-glycoprotein has an intramolecular dimer-like structure, each half of the molecule containing a cluster of six transmembrane sequences and a single ATP-binding sequence, the former followed by the latter. In contrast, white and brown proteins of Drosophila melanogaster, two of the members of the ABC superfamily which have been suggested to be involved in import of eye pigments into the cells, have a transposed structure; they have N-terminal ATP-binding sequences and C-terminal transmembrane segments, though they do not have an intramolecularly duplicated structure (9, 23).Brefeldin A (BFA) is a fungal metabolite which inhibits intracellular protein transport between the endoplasmic reticulum and the Golgi apparatus in animal cells and in yeasts (11,29). Interestingly, electron microscopical observation revealed that BFA caused disappearance of the Golgi apparatus in animal cells and induced aberrant membrane structures in Candida albicans (2,19). Recently it has been reported that BFA inhibits exchange of GDP for GTP bound to ADP ribosylation factor (ARF) on the Golgi membranes, resulting in perturbation of the budding process of transport vesicles (8,12). However, the BFA-sensitive cellular component(s), which is thought to be involved in the GDP-GTP exchange reaction of ARF on the Golgi membrane, is yet to be identified. To elucidate the molecular mechanism of action of BF...

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Brefeldin A blocks an early stage of protein transport in Candida albicans

Cited by 16 publications

References 40 publications

Cooperative domains define a unique host cell-targeting signal in Plasmodium falciparum -infected erythrocytes

Cooperative domains define a unique host cell-targeting signal in Plasmodium falciparum -infected erythrocytes

Inhibitors of cellular signalling are cytotoxic or block the budded-to-hyphal transition in the pathogenic yeast Candida albicans

bfr1+, a novel gene of Schizosaccharomyces pombe which confers brefeldin A resistance, is structurally related to the ATP-binding cassette superfamily

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