The Experts below are selected from a list of 3996 Experts worldwide ranked by ideXlab platform
Kenneth W. Nickerson - One of the best experts on this subject based on the ideXlab platform.
-
candida albicans czf1 and efg1 coordinate the response to Farnesol during quorum sensing white opaque thermal dimorphism and cell death
Eukaryotic Cell, 2013Co-Authors: Melanie L Langford, Kenneth W. Nickerson, Jessica C Hargarten, Krista D Patefield, Elizabeth Marta, Jill R Blankenship, Saranna Fanning, Audrey L. AtkinAbstract:ABSTRACT Quorum sensing by Farnesol in Candida albicans inhibits filamentation and may be directly related to its ability to cause both mucosal and systemic diseases. The Ras1-cyclic AMP signaling pathway is a target for Farnesol inhibition. However, a clear understanding of the downstream effectors of the morphological Farnesol response has yet to be unraveled. To address this issue, we screened a library for mutants that fail to respond to Farnesol. Six mutants were identified, and the czf1Δ/czf1Δ mutant was selected for further characterization. Czf1 is a transcription factor that regulates filamentation in embedded agar and also white-to-opaque switching. We found that Czf1 is required for filament inhibition by Farnesol under at least three distinct environmental conditions: on agar surfaces, in liquid medium, and when embedded in a semisolid agar matrix. Since Efg1 is a transcription factor of the Ras1-cyclic AMP signaling pathway that interacts with and regulates Czf1, an efg1Δ/efg1Δ czf1Δ/czf1Δ mutant was tested for filament inhibition by Farnesol. It exhibited an opaque-cell-like temperature-dependent morphology, and it was killed by low Farnesol levels that are sublethal to wild-type cells and both efg1Δ/efg1Δ and czf1Δ/czf1Δ single mutants. These results highlight a new role for Czf1 as a downstream effector of the morphological response to Farnesol, and along with Efg1, Czf1 is involved in the control of Farnesol-mediated cell death in C. albicans.
-
activity and toxicity of Farnesol towards candida albicans are dependent on growth conditions
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Melanie L Langford, Kenneth W. Nickerson, Sahar Hasim, Audrey L. AtkinAbstract:Farnesol interacts with Candida albicans as both a quorum-sensing molecule and toxic agent, but confusion abounds regarding which conditions promote these distinct responses. Farnesol sensitivity was measured when inoculum cell history and size, temperature, and growth media were altered. Parameters for Farnesol tolerance/sensitivity were defined, validating previous studies and identifying new variables, such as energy availability. This study clearly defines what Farnesol concentrations are lethal to C. albicans, based on environmental conditions.
-
cellular interactions of Farnesol a quorum sensing molecule produced by candida albicans
Future Microbiology, 2009Co-Authors: Melanie L Langford, Audrey L. Atkin, Kenneth W. NickersonAbstract:Farnesol is a quorum-sensing molecule produced by Candida albicans that has many effects, including filament inhibition of this polymorphic fungus. In the past 9 years, the effect of Farnesol on C. albicans has been reported in nearly 160 publications, with early work examining its influence on morphology. This article presents an update on the literature published since 2006, focusing on points that still need to be resolved as well as identifying possible artifacts that might interfere with this goal. In addition, the regulation of C. albicans Farnesol production, C. albicans’ resistance/sensitivity to Farnesol and the influence of Farnesol on other species as well as the host are discussed. It is intriguing that we still do not know precisely how Farnesol works, but interference with the Ras1–cAMP pathway is part of the story.
-
candida albicans tup1 is involved in Farnesol mediated inhibition of filamentous growth induction
Eukaryotic Cell, 2008Co-Authors: Bessie W Kebaara, Raluca Dumitru, Kenneth W. Nickerson, Dhammika H M L P Navarathna, Melanie L Langford, Audrey L. AtkinAbstract:Candida albicans is a dimorphic fungus that can interconvert between yeast and filamentous forms. Its ability to regulate morphogenesis is strongly correlated with virulence. Tup1, a transcriptional repressor, and the signaling molecule Farnesol are both capable of negatively regulating the yeast to filamentous conversion. Based on this overlap in function, we tested the hypothesis that the cellular response to Farnesol involves, in part, the activation of Tup1. Tup1 functions with the DNA binding proteins Nrg1 and Rfg1 as a transcription regulator to repress the expression of hypha-specific genes. The tup1/tup1 and nrg1/nrg1 mutants, but not the rfg1/rfg1 mutant, failed to respond to Farnesol. Treatment of C. albicans cells with Farnesol caused a small but consistent increase in both TUP1 mRNA and protein levels. Importantly, this increase corresponds with the commitment point, beyond which added Farnesol no longer blocks germ tube formation, and it correlates with a strong decrease in the expression of two Tup1-regulated hypha-specific genes, HWP1 and RBT1. Tup1 probably plays a direct role in the response to Farnesol because Farnesol suppresses the haploinsufficient phenotype of a TUP1/tup1 heterozygote. Farnesol did not affect EFG1 (a transcription regulator of filament development), NRG1, or RFG1 mRNA levels, demonstrating specific gene regulation in response to Farnesol. Furthermore, the tup1/tup1 and nrg1/nrg1 mutants produced 17- and 19-fold more Farnesol, respectively, than the parental strain. These levels of excess Farnesol are sufficient to block filamentation in a wild-type strain. Our data are consistent with the role of Tup1 as a crucial component of the response to Farnesol in C. albicans.
-
exogenous Farnesol interferes with the normal progression of cytokine expression during candidiasis in a mouse model
Infection and Immunity, 2007Co-Authors: Dhammika H M L P Navarathna, Kenneth W. Nickerson, Gerald E Duhamel, Thomas R Jerrels, Thomas M PetroAbstract:Candida albicans, a dimorphic fungus composed of yeast and mycelial forms, is the most common human fungal pathogen. Th1 cytokines such as interleukin-2 (IL-2), gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha), which are induced by macrophage IL-12, are critical to resistance against systemic candidiasis, while Th2 cytokines such as IL-4 and IL-5 are less critical. Farnesol is a quorum-sensing molecule produced by C. albicans that controls the formation of mycelia but is also a virulence factor. To determine whether Farnesol enhances the virulence of C. albicans by modulating the production of Th1 and Th2 cytokines, mice were pretreated with Farnesol prior to intravenous infection with a sublethal dose of Farnesol-producing C. albicans. Production of IL-2, IL-4, IL-5, TNF-alpha, IFN-gamma, and IL-12 was evaluated by bead-array flow cytometry and enzyme-linked immunosorbent assay. Mice exhibited an elevation in serum TNF-alpha levels at 48 h and an elevation in IFN-gamma and IL-12 levels at 6 to 12 h after infection with C. albicans. Pretreatment with Farnesol significantly reduced the elevation of both IFN-gamma and IL-12 but not TNF-alpha. In contrast, mice pretreated with Farnesol exhibited an unexpected elevation in IL-5 levels. To determine whether Farnesol has a direct effect on macrophage production of IL-12, peritoneal macrophages were pretreated with Farnesol prior to stimulation with IFN-gamma plus lipopolysaccharide (LPS). Farnesol inhibited production of both IL-12 p40 and p70 from IFN-gamma/LPS-stimulated macrophages. Therefore, the role of Farnesol in systemic candidiasis is likely due to its ability to inhibit the critical Th1 cytokines IFN-gamma and IL-12 and perhaps to enhance a Th2 cytokine, IL-5.
Jacob M. Hornby - One of the best experts on this subject based on the ideXlab platform.
-
effect of Farnesol on a mouse model of systemic candidiasis determined by use of a dpp3 knockout mutant of candida albicans
Infection and Immunity, 2007Co-Authors: Dhammika H M L P Navarathna, Jacob M. Hornby, Navasona Krishnan, Anne M Parkhurst, Gerald E Duhamel, Kenneth W. NickersonAbstract:This work extends our previous observation that the fungus Candida albicans secretes micromolar levels of Farnesol and that accumulation of Farnesol in vitro prevents the yeast-to-mycelium conversion in a quorum-sensing manner. What does Farnesol do in vivo? The purpose of this study was to determine the role of Farnesol during infection with a well-established mouse model of systemic candidiasis with C. albicans A72 administered by tail vein injection. This question was addressed by altering both endogenous and exogenous Farnesol. For endogenous Farnesol, we created a knockout mutation in DPP3, the gene encoding a phosphatase which converts farnesyl pyrophosphate to Farnesol. This mutant (KWN2) produced six times less Farnesol and was ca. 4.2 times less pathogenic than its SN152 parent. The strain with DPP3 reconstituted (KWN4) regained both its Farnesol production levels and pathogenicity. These mutants (KWN1 to KWN4) retained their full dimorphic capability. With regard to exogenous Farnesol, Farnesol was administered either intraperitoneally (i.p.) or orally in the drinking water. Mice receiving C. albicans intravenously and Farnesol (20 mM) orally had enhanced mortality (P < 0.03). Similarly, mice (n = 40) injected with 1.0 ml of 20 mM Farnesol i.p. had enhanced mortality (P < 0.03), and the onset of mortality was 30 h sooner than for mice which received a control injection without Farnesol. The effect of i.p. Farnesol was more pronounced (P < 0.04) when mice were inoculated with a sublethal dose of C. albicans. These mice started to die 4 days earlier, and the percent survival on day 6 postinoculation (p.i.) was five times lower than for mice receiving C. albicans with control i.p. injections. In all experiments, mice administered Farnesol alone or Tween 80 alone remained normal throughout a 14-day observation period. Finally, beginning at 12 h p.i., higher numbers of C. albicans cells were detected in kidneys from mice receiving i.p. Farnesol than in those from mice receiving control i.p. injections. Thus, reduced endogenous Farnesol decreased virulence, while providing exogenous Farnesol increased virulence. Taken together, these data suggest that Farnesol may play a role in disease pathogenesis, either directly or indirectly, and thus may represent a newly identified virulence factor.
-
Farnesol induced apoptosis in aspergillus nidulans reveals a possible mechanism for antagonistic interactions between fungi
Molecular Microbiology, 2006Co-Authors: Camile P Semighini, Raluca Dumitru, Jacob M. Hornby, Kenneth W. Nickerson, Steven D HarrisAbstract:The dimorphic fungus Candida albicans secretes Farnesol, which acts as a quorum-sensing molecule and prevents the yeast to mycelium conversion. In this study we examined the effect of Farnesol in the filamentous fungus Aspergillus nidulans. We show that externally added Farnesol has no effect on hyphal morphogenesis; instead, it triggers morphological features characteristic of apoptosis. Additional experiments suggest that mitochondria and reactive oxygen species (ROS) participate in Farnesol-induced apoptosis. Moreover, the effects of Farnesol appear to be mediated by the FadA heterotrimeric G protein complex. Because A. nidulans does not secrete detectable amounts of Farnesol, we propose that it responds to Farnesol produced by other fungi. In agreement with this notion, growth and development were impaired in a Farnesol-dependent manner when A. nidulans was co-cultivated with C. albicans. Taken together, our data suggest that Farnesol, in addition to its quorum-sensing function that regulates morphogenesis, is also employed by C. albicans to reduce competition from other microbes.
-
Farnesol concentrations required to block germ tube formation in Candida albicans in the presence and absence of serum.
Applied and environmental microbiology, 2005Co-Authors: Daniel D. Mosel, Raluca Dumitru, Jacob M. Hornby, Audrey L. Atkin, Kenneth W. NickersonAbstract:Concentrations of (E,E)-Farnesol needed to inhibit germ tube formation were determined for Candida albicans strains A72 and SC5314 by using six different conditions known to trigger germination. For defined media, 1 to 2 μM Farnesol was sufficient. However, with serum at 2 to 20%, up to 250 μM Farnesol was required. Farnesol blocked germ tube formation but did not block elongation of existing germ tubes.
-
enhanced production of Farnesol by candida albicans treated with four azoles
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: Jacob M. Hornby, Kenneth W. NickersonAbstract:The dimorphic fungus Candida albicans excretes Farnesol, which is produced enzymatically from the sterol biosynthetic intermediate farnesyl pyrophosphate. Inhibition of C. albicans by four azole antifungals, fluconazole, ketoconazole, miconazole, and clotrimazole, caused elevated Farnesol production (10- to 45-fold). Furthermore, Farnesol production occurs in both laboratory strains and clinical isolates (J. M. Hornby et al., Appl. Environ. Microbiol. 67:2982-2992, 2001) of C. albicans.
-
Farnesol biosynthesis in candida albicans cellular response to sterol inhibition by zaragozic acid b
Antimicrobial Agents and Chemotherapy, 2003Co-Authors: Jacob M. Hornby, Bessie W Kebaara, Kenneth W. NickersonAbstract:The dimorphic fungus Candida albicans produces Farnesol as a quorum-sensing molecule that regulates cellular morphology. The biosynthetic origin of Farnesol has been resolved by treating these cells with zaragozic acid B, a potent inhibitor of squalene synthase in the sterol biosynthetic pathway. Treatment with zaragozic acid B leads to an eightfold increase in the amount of Farnesol produced by C. albicans . Furthermore, C. albicans cell extracts contain enzymatic activity to convert [ 3 H]farnesyl pyrophosphate to [ 3 H]Farnesol. Many common antifungal antibiotics (e.g., zaragozic acids, azoles, and allylamines) target steps in sterol biosynthesis. We suggest that the fungicidal activity of zaragozic acid derives in large part from the accumulation of Farnesol that accompanies the inhibition of sterol biosynthesis.
Robert D Simoni - One of the best experts on this subject based on the ideXlab platform.
-
Farnesol as a regulator of hmg coa reductase degradation characterization and role of farnesyl pyrophosphatase
Archives of Biochemistry and Biophysics, 1997Co-Authors: Thomas E Meigs, Robert D SimoniAbstract:We have recently reported that the isoprenoid compound Farnesol accelerates degradation of the cholesterologenic enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, when added to cultured cells. We have thus proposed that Farnesol is a required nonsterol regulator of this degradation event (T. E. Meigs, D. S. Roseman, and R. D. Simoni, 1996, J. Biol. Chem. 271, 7916-7922). In this report, we have studied the enzyme farnesyl pyrophosphatase (FPPase) in Chinese hamster ovary cells. We demonstrate that FPPase activity increases under conditions of increased metabolic flow through the isoprenoid pathway. Also, we show that a nonhydrolyzable analog of farnesyl pyrophosphate, an isoprenoid (phosphinylmethyl)phosphonate, inhibits FPPase in vitro, and when added to cells this inhibitor blocks the mevalonate-dependent, sterol-induced degradation of HMG-CoA reductase. Furthermore, exogenous Farnesol overcomes the effect of this inhibitor. These results suggest an isoprenoid-mediated regulatory mechanism governing intracellular Farnesol production and support the hypothesis that Farnesol is a nonsterol regulator of reductase degradation.
-
regulation of 3 hydroxy 3 methylglutaryl coenzyme a reductase degradation by the nonsterol mevalonate metabolite Farnesol in vivo
Journal of Biological Chemistry, 1996Co-Authors: Thomas E Meigs, Daniel S Roseman, Robert D SimoniAbstract:We have previously reported that degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in the isoprenoid pathway leading to cholesterol production, can be accelerated in cultured cells by the addition of farnesyl compounds, which are thought to mimic a natural, nonsterol mevalonate metabolite(s). In this paper we report accelerated reductase degradation by the addition of Farnesol, a natural product of mevalonate metabolism, to intact cells. We demonstrate that this regulation is physiologically meaningful, shown by its blockage by several inhibitory conditions that are known to block the degradation induced by mevalonate addition. We further show that intracellular Farnesol levels increase significantly after mevalonate addition. Based on these results, we conclude that Farnesol is a nonsterol, mevalonate-derived product that plays a role in accelerated reductase degradation. Our conclusion is in agreement with a previous report (Correll, C. C., Ng, L., and Edwards, P. A. (1994) J. Biol. Chem. 269, 17390-17393), in which an in vitro system was used to study the effect of Farnesol on reductase degradation. However, the apparent stimulation of degradation in vitro appears to be due to nonphysiological processes. Our findings demonstrate that in vitro, Farnesol causes reductase to become detergent insoluble and thus lost from immunoprecipitation experiments, yielding apparent degradation. We further show that another resident endoplasmic reticulum protein, calnexin, similarly gives the appearance of protein degradation after Farnesol addition in vitro. However, after the addition of Farnesol to cells in vivo, calnexin remains stable, whereas reductase is degraded, providing further evidence that the in vivo effects of Farnesol are physiologically meaningful and specific for reductase, whereas the in vitro effects are not.
Peter A Edwards - One of the best experts on this subject based on the ideXlab platform.
-
sterols and isoprenoids signaling molecules derived from the cholesterol biosynthetic pathway
Annual Review of Biochemistry, 1999Co-Authors: Peter A Edwards, Johan EricssonAbstract:▪ Abstract Compounds derived from the isoprenoid/cholesterol biosynthetic pathway have recently been shown to have novel biological activities. These compounds include certain sterols, oxysterols, Farnesol, and geranylgeraniol, as well as the diphosphate derivatives of isopentenyl, geranyl, farnesyl, geranylgeranyl, and presqualene. They regulate transcriptional and post-transcriptional events that in turn affect lipid synthesis, meiosis, apoptosis, developmental patterning, protein cleavage, and protein degradation.
-
identification of Farnesol as the non sterol derivative of mevalonic acid required for the accelerated degradation of 3 hydroxy 3 methylglutaryl coenzyme a reductase
Journal of Biological Chemistry, 1994Co-Authors: C C Correll, Peter A EdwardsAbstract:The degradation of the microsomal enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase is highly regulated and is dependent on both a sterol and non-sterol derivative of mevalonic acid (MVA). We recently proposed that the non-sterol component is derived from farnesyl diphosphate (FPP), presqualene pyrophosphate, or squalene (Correll, C. C. and Edwards, P. A. (1994) J. Biol. Chem. 269, 633-638). In the current study, we have used digitonin-permeabilized cells to further define this MVA-derived non-sterol component required for the regulated degradation of HMG-CoA reductase. The addition of either FPP or Farnesol to digitonin-permeabilized cells resulted in a rapid and dose-dependent degradation of HMG-CoA reductase. The effect of FPP, but not Farnesol, was blocked by the phosphatase inhibitor sodium fluoride. The enhanced degradation of HMG-CoA reductase in permeabilized cells specifically required Farnesol, since the addition of any of the structurally related isoprenoids geraniol, geranyl diphosphate, geranylgeranyl diphosphate, nerolidol, or all-cis-Farnesol, or of the non-sterol squalene to the permeabilized cells did not stimulate enzyme degradation. The present studies demonstrate for the first time that the accelerated degradation of HMG-CoA reductase can be initiated in vitro. Further, since Farnesol is shown to be specifically required for the enhanced degradation of the enzyme in vitro, we propose that this isoprenoid alcohol is important in this process in intact cells.
Thomas E Meigs - One of the best experts on this subject based on the ideXlab platform.
-
Farnesol as a regulator of hmg coa reductase degradation characterization and role of farnesyl pyrophosphatase
Archives of Biochemistry and Biophysics, 1997Co-Authors: Thomas E Meigs, Robert D SimoniAbstract:We have recently reported that the isoprenoid compound Farnesol accelerates degradation of the cholesterologenic enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, when added to cultured cells. We have thus proposed that Farnesol is a required nonsterol regulator of this degradation event (T. E. Meigs, D. S. Roseman, and R. D. Simoni, 1996, J. Biol. Chem. 271, 7916-7922). In this report, we have studied the enzyme farnesyl pyrophosphatase (FPPase) in Chinese hamster ovary cells. We demonstrate that FPPase activity increases under conditions of increased metabolic flow through the isoprenoid pathway. Also, we show that a nonhydrolyzable analog of farnesyl pyrophosphate, an isoprenoid (phosphinylmethyl)phosphonate, inhibits FPPase in vitro, and when added to cells this inhibitor blocks the mevalonate-dependent, sterol-induced degradation of HMG-CoA reductase. Furthermore, exogenous Farnesol overcomes the effect of this inhibitor. These results suggest an isoprenoid-mediated regulatory mechanism governing intracellular Farnesol production and support the hypothesis that Farnesol is a nonsterol regulator of reductase degradation.
-
regulation of 3 hydroxy 3 methylglutaryl coenzyme a reductase degradation by the nonsterol mevalonate metabolite Farnesol in vivo
Journal of Biological Chemistry, 1996Co-Authors: Thomas E Meigs, Daniel S Roseman, Robert D SimoniAbstract:We have previously reported that degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in the isoprenoid pathway leading to cholesterol production, can be accelerated in cultured cells by the addition of farnesyl compounds, which are thought to mimic a natural, nonsterol mevalonate metabolite(s). In this paper we report accelerated reductase degradation by the addition of Farnesol, a natural product of mevalonate metabolism, to intact cells. We demonstrate that this regulation is physiologically meaningful, shown by its blockage by several inhibitory conditions that are known to block the degradation induced by mevalonate addition. We further show that intracellular Farnesol levels increase significantly after mevalonate addition. Based on these results, we conclude that Farnesol is a nonsterol, mevalonate-derived product that plays a role in accelerated reductase degradation. Our conclusion is in agreement with a previous report (Correll, C. C., Ng, L., and Edwards, P. A. (1994) J. Biol. Chem. 269, 17390-17393), in which an in vitro system was used to study the effect of Farnesol on reductase degradation. However, the apparent stimulation of degradation in vitro appears to be due to nonphysiological processes. Our findings demonstrate that in vitro, Farnesol causes reductase to become detergent insoluble and thus lost from immunoprecipitation experiments, yielding apparent degradation. We further show that another resident endoplasmic reticulum protein, calnexin, similarly gives the appearance of protein degradation after Farnesol addition in vitro. However, after the addition of Farnesol to cells in vivo, calnexin remains stable, whereas reductase is degraded, providing further evidence that the in vivo effects of Farnesol are physiologically meaningful and specific for reductase, whereas the in vitro effects are not.
