Farnesol-induced growth inhibition in Saccharomyces cerevisiae by a cell cycle mechanism

Propagation of the yeast prion [PSIP rions (infectious proteins) are proteins that are normally soluble but autocatalytically propagate as amyloid, which is a fibrous polymer-like aggregate rich in ␤-sheet secondary structure (1). Normally folded mammalian prion protein has a high ␣-helical content, but its aggregated form contains much more ␤-sheet and is highly resistant to proteolysis. When this autocatalytic conversion occurs on a large scale in the central nervous system, the amyloid form accumulates and is associated with the neurodegeneration in fatal diseases such as scrapie in sheep, bovine spongiform encephalopathy in cows, and Creutzfeld-Jacob disease in humans (2). Other proteins form amyloid in an autocatalytic manner, but only prion protein is infectious.Prions also occur in yeast (3). The best-characterized yeast prion proteins are Sup35p, a translation termination factor, and Ure2p, which is involved in nitrogen metabolism (4). More recently, Rnq1p was identified as a prion protein, and New1p was shown to contain a domain that can substitute for the priondetermining region of Sup35p (5-7). Amyloidogenic yeast prion proteins have an Asn͞Gln-rich prion-forming domain that, like mammalian prion protein, can be converted to a ␤-sheet-rich, protease-resistant conformation in an autocatalytic manner. When yeast cells containing soluble Sup35p, for example, are mated to cells containing the prion form of Sup35p, the soluble form is converted to the aggregated form, which then continues to propagate as the yeast divide. is not yet understood. Lindquist and colleagues (11, 13) have suggested that the ability of Hsp104 both to nucleate Sup35p aggregation and to break up these aggregates plays a role in maintaining [PSI ϩ ]. On the other hand, others have suggested that Hsp104 is required only to break up aggregates to replicate them so that they are passed on to daughter cells when yeast divide (14-16). It was further proposed that Hsp104 breaks up only the small aggregates, whereas large aggregates form dead-end complexes unable to propagate the prion trait (15,(17)(18)(19).Investigations into the mechanism of action of Hsp104 have been facilitated by experiments showing that Hsp104 in vivo can be inactivated by treating yeast with low levels of guanidinehydrochloride (Gdn) (20)(21)(22). Whereas it was demonstrated many years ago that such treatment cures [PSI ϩ ], recently it was shown that Gdn acts by inhibiting Hsp104 ATPase activity (23,24). Because Gdn inactivates Hsp104 immediately, kinetics of [PSI ϩ ] curing after this inactivation can be monitored straightforwardly. When growing cells are exposed to Gdn there is a lag phase during which no curing occurs followed by a linear increase in the number of cured cells over time (25).These kinetic studies have supported the model that Hsp104 acts by breaking up prion polymers, thereby generating new prion ''seeds.'' During the lag phase that occurs after Hsp104 activity is inhibited, the prion polymers or seeds are thought to grow in size but, failing to...

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“…Essentially identical results were obtained when cell division was reversibly arrested by treatment with farnesol (27). As shown in Fig.…”

Section: Resultssupporting

confidence: 73%

“…To arrest cell division, cells were treated with 50 M ␣-factor (Zymo Research) or 100 M farnesol (Sigma). This latter treatment arrests cell division by inhibiting DNA ligase and histone acetyltransferase (27).…”

mentioning

confidence: 99%

Curing of yeast [PSI ⁺ ] prion by guanidine inactivation of Hsp104 does not require cell division

Greene

Masison

et al. 2005

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

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“…Among the recently identified quorum-sensing molecules is the sesquiterpene alcohol farnesol, which has been shown to affect the morphogenesis and biofilm formation of the yeast C. albicans (21,32). Farnesol is naturally found in essential oils of citrus fruits and was shown to be devoid of toxic effects and nonmutagenic in vitro and in vivo (9,24,26). Farnesol exposure significantly affected the rate of glucan synthesis in S. mutans, the main polysaccharide in the biofilm matrix, and consequently reduced the accumulation and biomass of the biofilms (24).…”

Section: Discussionmentioning

confidence: 99%

Effect of Farnesol on Staphylococcus aureus Biofilm Formation and Antimicrobial Susceptibility

Jabra‐Rizk

Meiller²,

James

et al. 2006

Antimicrob Agents Chemother

307

246

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Staphylococcus aureus is among the leading pathogens causing bloodstream infections able to form biofilms on host tissue and indwelling medical devices and to persist and cause disease. Infections caused by S. aureus are becoming more difficult to treat because of increasing resistance to antibiotics. In a biofilm environment particularly, microbes exhibit enhanced resistance to antimicrobial agents. Recently, farnesol was described as a quorum-sensing molecule with possible antimicrobial properties. In this study, the effect of farnesol on methicillin-resistant and -susceptible strains of S. aureus was investigated. With viability assays, biofilm formation assessment, and ethidium bromide uptake testing, farnesol was shown to inhibit biofilm formation and compromise cell membrane integrity. The ability of farnesol to sensitize S. aureus to antimicrobials was assessed by agar disk diffusion and broth microdilution methods. For both strains of staphylococci, farnesol was only able to reverse resistance at a high concentration (150 M). However, it was very successful at enhancing the antimicrobial efficacy of all of the antibiotics to which the strains were somewhat susceptible. Therefore, synergy testing of farnesol and gentamicin was performed with static biofilms exposed to various concentrations of both agents. Plate counts of harvested biofilm cells at 0, 4, and 24 h posttreatment indicated that the combined effect of gentamicin at 2.5 times the MIC and farnesol at 100 M (22 g/ml) was able to reduce bacterial populations by more than 2 log units, demonstrating synergy between the two antimicrobial agents. This observed sensitization of resistant strains to antimicrobials and the observed synergistic effect with gentamicin indicate a potential application for farnesol as an adjuvant therapeutic agent for the prevention of biofilm-related infections and promotion of drug resistance reversal.

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“…The effects of farnesol on human cells is particularly relevant in light of reports that subinhibitory concentrations of some antifungal compounds lead to increased production of farnesol by C. albicans (31,59). Machida et al reported that farnesol induces mitochondrion-generated reactive oxygen species and growth arrest in S. cerevisiae yeast cells after a 30-min treatment with farnesol but not after treatment with other isoprenoid compounds (52,53) and have proposed that farnesol inhibits a phosphatidylinositol-type signaling pathway S. cerevisiae (54). Several studies have shown that farnesol may also participate in fungal-bacterial interactions.…”

Section: Multiple Roles Of Autoregulatory Secreted Productsmentioning

confidence: 99%

Talking to Themselves: Autoregulation and Quorum Sensing in Fungi

2006

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Extracellular autoinducing compounds in the supernatants of microbial cultures were first recognized for their roles in the induction of genetic competence in gram-positive bacteria (17,94) and in the regulation of light production in marine vibrios (60). In 1994, this form of population-level regulation in microbes was dubbed "quorum sensing" since it enabled bacterial cells to chemically measure the density of the surrounding population (18). Subsequently, many examples of cell densitydependent regulation by extracellular factors have been found in diverse microorganisms. The widespread incidence of diverse quorum-sensing systems strongly suggests that regulation in accordance with cell density is important for the success of microbes in many environments (see references 25 and 95 for reviews).Cell density-dependent regulatory networks in microorganisms generally control processes that involve cell-cell interactions, such as group motility (10, 37) and the formation of multicellular structures (67,93,95). In a wide array of environmental and medically relevant bacteria, the development, maintenance, and dispersion of multicellular, surface-associated biofilms are in part controlled by quorum-sensing regulatory pathways (for reviews, see references 67 and 93). The uptake of extracellular DNA is often regulated in accordance with cell density presumably to enhance the chances of taking up DNA from closely related strains. For some bacteria, a link between the competence and biofilm formation has been established (69, 93). Both pathogens and symbionts that live in association with plant or animal hosts often use quorum sensing to regulate factors involved in microbe-host interactions (20,86,96). Quorum-sensing regulation may allow host-associated microbes to delay detection until an effective population has formed in the appropriate niche within the host.Recently, it has become apparent that fungi, like bacteria, also use quorum regulation to affect population-level behaviors such as biofilm formation and pathogenesis. Considering the extent to which quorum-sensing regulation controls important processes in many distantly related bacterial genera, it is not surprising that cell density-dependent regulation also appears to be prevalent in diverse fungal species. Because fungal quorum sensing has been most extensively studied in Candida albicans, a dimorphic opportunistic pathogen, the majority of this review focuses on the details of quorum-sensing regulation in this fungus. A discussion of other fungi that appear to use quorum-sensing regulation and the identities of other known fungal signaling molecules are presented, and potential connections between mating in fungi and cell density-dependent regulation are explored. The review will conclude with points relating to the ecology of quorum sensing and a discussion of quorum-sensing networks as potential targets for antifungal therapies.

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Farnesol-induced growth inhibition in Saccharomyces cerevisiae by a cell cycle mechanism

Cited by 80 publications

References 28 publications

Curing of yeast [PSI ⁺ ] prion by guanidine inactivation of Hsp104 does not require cell division

Curing of yeast [PSI ⁺ ] prion by guanidine inactivation of Hsp104 does not require cell division

Effect of Farnesol on Staphylococcus aureus Biofilm Formation and Antimicrobial Susceptibility

Talking to Themselves: Autoregulation and Quorum Sensing in Fungi

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Farnesol-induced growth inhibition in Saccharomyces cerevisiae by a cell cycle mechanism

Cited by 80 publications

References 28 publications

Curing of yeast [PSI + ] prion by guanidine inactivation of Hsp104 does not require cell division

Curing of yeast [PSI + ] prion by guanidine inactivation of Hsp104 does not require cell division

Effect of Farnesol on Staphylococcus aureus Biofilm Formation and Antimicrobial Susceptibility

Talking to Themselves: Autoregulation and Quorum Sensing in Fungi

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Product

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Curing of yeast [PSI ⁺ ] prion by guanidine inactivation of Hsp104 does not require cell division

Curing of yeast [PSI ⁺ ] prion by guanidine inactivation of Hsp104 does not require cell division