The Quorum-Sensing Molecules Farnesol/Homoserine Lactone and Dodecanol Operate via Distinct Modes of Action in Candida albicans

Hall, Rebecca; Turner, Kara; Chaloupka, James; Cottier, Fabien; Sordi, Luisa De; Sanglard, Dominique; Levin, Lonny R.; Buck, Jochen; Mühlschlegel, Fritz A.

doi:10.1128/ec.05060-11

Cited by 118 publications

(142 citation statements)

References 59 publications

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“…The preferential requirement of Tpk2 for NRG1 transcriptional down-regulation is consistent with the distinct but overlapping roles reported for Tpk1 and Tpk2 in hyphal development (20). Farnesol is thought to affect hyphal initiation by inhibiting the Ras1-Cyr1 pathway (8,21,22). Consistent with this notion, we detected about 23% of the NRG1 transcript left after 30 min in farnesol-containing medium at 37°C, which was higher than without farnesol (Fig.…”

Section: Resultssupporting

confidence: 78%

“…In addition to farnesol, other quorumsensing molecules in the host's gut microbiota may also regulate hyphal development of C. albicans. For example, the quorumsensing molecule 3-oxo-C 12 -homoserine lactone, which is secreted by Pseudomonas aeruginosa, can also inhibit the yeast-to-hyphal transition (2,22,44). Other conditions unique to the host GI tract, such as high iron levels, can also contribute to the growth state of the commensal pathogen (45).…”

Section: Discussionmentioning

confidence: 99%

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Quorum sensing controls hyphal initiation in Candida albicans through Ubr1-mediated protein degradation

Lü

Unoje

et al. 2014

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

123

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Candida albicans is the most common cause of invasive fungal infections in humans. Its ability to undergo the morphological transition from yeast to hyphal growth forms is critical for its pathogenesis. Hyphal initiation requires the activation of the cAMP-PKA pathway, which down-regulates the expression of NRG1, the major repressor of hyphal development. Hyphal initiation also requires inoculation of a small amount of C. albicans cells from overnight culture to fresh medium. This inoculation releases the inhibition from farnesol, a quorum-sensing molecule of C. albicans, that accumulated in the spent medium. Here, we show that farnesol inhibits hyphal initiation mainly through blocking the protein degradation of Nrg1. Through screening a kinase mutant library, we identified Sok1 as the kinase required for Nrg1 degradation during inoculation. SOK1 expression is transiently activated on inoculation during hyphal initiation, and overexpression of SOK1 overcomes the farnesol-mediated inhibition of hyphal initiation. Screening a collection of transcription factor mutants, the homeodomain-containing transcription repressor Cup9 is found to be responsible for the repression of SOK1 expression in response to farnesol inhibition. Interestingly, farnesol inhibits Cup9 degradation mediated by the N-end rule E3 ubiquitin ligase, Ubr1. Therefore, hyphal initiation requires both the cAMP-PKA pathway-dependent transcriptional down-regulation of NRG1 and Sok1-mediated degradation of Nrg1 protein. The latter is triggered by the release from farnesol inhibition of Cup9 degradation and consequently, derepression of SOK1 transcription. Neither pathway alone is sufficient for hyphal initiation.

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Quorum sensing controls hyphal initiation in Candida albicans through Ubr1-mediated protein degradation

Lü

Unoje

et al. 2014

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

123

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“…This autoregulatory molecule prevents yeast cells from germinating through inhibition of the Ras1-cAMP pathway (11,12) via direct inhibition of Cyr1 activity (19). While farnesol has been proposed to be a morphological regulatory signal, the effects of farnesol on the hypha-to-yeast transition are less clear.…”

mentioning

confidence: 98%

Farnesol and Cyclic AMP Signaling Effects on the Hypha-to-Yeast Transition in Candida albicans

et al. 2012

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b Candida albicans, a fungal pathogen of humans, regulates its morphology in response to many environmental cues and this morphological plasticity contributes to virulence. Farnesol, an autoregulatory molecule produced by C. albicans, inhibits the induction of hyphal growth by inhibiting adenylate cyclase (Cyr1). The role of farnesol and Cyr1 in controlling the maintenance of hyphal growth has been less clear. Here, we demonstrate that preformed hyphae transition to growth as yeast in response to farnesol and that strains with increased cyclic AMP (cAMP) signaling exhibit more resistance to farnesol. Exogenous farnesol did not induce the hypha-to-yeast transition in mutants lacking the Tup1 or Nrg1 transcriptional repressors in embedded conditions. Although body temperature is not required for embedded hyphal growth, we found that the effect of farnesol on the hypha-to-yeast transition varies inversely with temperature. Our model of Cyr1 activity being required for filamentation is also supported by our liquid assay data, which show increased yeast formation when preformed filaments are treated with farnesol. Together, these data suggest that farnesol can modulate morphology in preformed hyphal cells and that the repression of hyphal growth maintenance likely occurs through the inhibition of cAMP signaling.

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“…The enhanced farnesol could reduce the cAMP synthesis though inhibiting the activity of Cdc35 and lead to the ROS accumulation. 30,31) The reduced cAMP level and stimulated ROS by RAB could also facilitate the antifungal effect of FLC against C. albicans.…”

Section: Discussionmentioning

confidence: 99%

Retigeric Acid B Enhances the Efficacy of Azoles Combating the Virulence and Biofilm Formation of <i>Candida albicans</i>

Chang

Liu

Zhang

et al. 2012

Biological & Pharmaceutical Bulletin

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Candida albicans is one of the most prevalent human opportunistic pathogens. C. albicans undergoes a yeast-to-hyphal transition that has been identified as a virulence factor as well as a critical element for mature biofilm formation. A previous study in our lab showed retigeric acid B (RAB), a lichen derived pentacyclic triterpenoid, displayed synergistic antifungal activity with azoles. We now showed that this combination also proved to be adequate in combating the formation of hyphae in vitro. In vivo tests with mice demonstrated RAB could markedly enhance the efficacy of fluconazole to promote the host's longevity through inhibiting hyphae formation and adherence to host cells. It was also observed that RAB and azoles interacted synergistically to block the formation of biofilm. Our data suggested the attenuated yeast-to-hyphal switch contributed to the defect of mature biofilm formation. Moreover, quantitative real-time polymerase chain reaction (qPCR) analysis showed RAB could reduce the transcript level of MDR1, a multidrug efflux pump, and caused a slight transcriptional reduction for another drug pump related gene CDR1. Taken together, our work provides a potential application to combat candidiasis using the combination of RAB and azoles.Key words hyphae; biofilm; virulence; synergistic; Candida albicans Candida albicans is a dimorphic pathogen which undergoes the transition from yeast form to hyphal form according to the growing condition.1,2) Hyphae filaments have the ability to penetrate tissue and escape immune cell recognition, which results in systemic infection in humans.3) Filamentation is also required for normal biofilm formation and development. 4,5) A biofilm is a protected niche for microorganisms in which they are less susceptible to antibiotic treatment and can create a source of persistent infection. 4,6) The development of C. albicans biofilms is clinically significant since cells within biofilm are more resistant to traditional antifungal agents and host immune factors, making biofilm-associated C. albicans infections much more difficult to treat. 7) A C. albicans biofilm consists of a network of yeasts, pseudohyphae and hyphae encased in a self-produced extracellular matrix. The formation of a biofilm initiates with the adherence of blastopores to a surface. Following adhesion, an extracellular matrix is secreted to encase the community of organisms. 4) During the process, yeast cells differentiate into hyphae, and form a stable structure. Inhibition of the yeast-to-hyphal transition could be used as an effected approach to prevent biofilm formation, as hyphae defective mutants have deficiencies in producing a substantial biofilm. 8)Lichens are a useful source of multiple secondary compounds which exhibit excellent bioactivities such as antibiotic, antifungal, antiviral properties.9,10) Our previous study reported that retigeric acid B (RAB) isolated from the lichen Lobaria kurokawae has a synergistic effect to reduce the minimum inhibitory concentration (MIC) of azoles, especially in...

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The Quorum-Sensing Molecules Farnesol/Homoserine Lactone and Dodecanol Operate via Distinct Modes of Action in Candida albicans

Cited by 118 publications

References 59 publications

Quorum sensing controls hyphal initiation in Candida albicans through Ubr1-mediated protein degradation

Quorum sensing controls hyphal initiation in Candida albicans through Ubr1-mediated protein degradation

Farnesol and Cyclic AMP Signaling Effects on the Hypha-to-Yeast Transition in Candida albicans

Retigeric Acid B Enhances the Efficacy of Azoles Combating the Virulence and Biofilm Formation of <i>Candida albicans</i>

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