Candida albicans is a clinically important dimorphic fungus that exhibits either a budding yeast or a mycelial-hyphal or pseudohyphal growth, depending on environmental conditions. The yeast-to-mycelia morphologic transition, which is generally regarded as an important virulence determinant, depends on the inoculum size of liquid cultures. The yeast form is favored when cultures are inoculated at \u3e 106 cells∙mL–1, whereas the mycelial form is favored at inoculum densities \u3c 106∙mL–1. Farnesoic acid (FA) and farnesol (FOH) are two related sesquiterpene quorum- sensing molecules that, upon accumulation, prevent the yeast-to-mycelial conversion. Oh et al. showed that C. albicans strain ATCC 10231 excretes FA, while Hornby et al. showed that C. albicans A72 and SC5314 excrete FOH. Subsequent work indicated that 10231 was the only isolate of C. albicans that fails to produce detectable FOH. Moreover, when tested on C. albicans A72, FA had only 3.2% of the hyphal-inhibitory activity relative to FOH. These observations raised two questions: 1., Do FOH and FA block mycelial development via the same molecular mechanism; and 2., What is the biochemical or physiologic difference in strain 10231 that underlies excretion of FA and not FOH?
Do farnesol and farnesoic acid share a common mechanism of action?
An apparent paradox in the regulation of hyphal morphogenesis by CaPho81p
Why does C. albicans strain 10231 secrete farnesoic acid, while other C. albicans strains secrete farnesol

Nickerson, Kenneth

Riekhof, Wayne R.

English

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University of Nebraska - Lincoln 
DigitalCommons@University of Nebraska - Lincoln 
Kenneth Nickerson Papers Papers in the Biological Sciences 
2017 
Quorum sensing in Candida albicans: farnesol versus farnesoic 
acid 
Wayne R. Riekhof 
Kenneth Nickerson 
Follow this and additional works at: https://digitalcommons.unl.edu/bioscinickerson 
 Part of the Environmental Microbiology and Microbial Ecology Commons, Other Life Sciences 
Commons, and the Pathogenic Microbiology Commons 
This Article is brought to you for free and open access by the Papers in the Biological Sciences at 
DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Kenneth Nickerson Papers 
by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. 
COMMENTARY
Quorum sensing in Candida albicans: farnesol versus
farnesoic acid
Wayne R. Riekhof and Kenneth W. Nickerson
School of Biological Sciences, University of Nebraska – Lincoln, Lincoln, NE, USA
Candida albicans is a clinically important dimorphic
fungus that exhibits either a budding yeast or a myce-
lial-hyphal or pseudohyphal growth, depending on
environmental conditions. The yeast-to-mycelia mor-
phologic transition, which is generally regarded as an
important virulence determinant [1], depends on the
inoculum size of liquid cultures. The yeast form is
favored when cultures are inoculated at > 106
cellsmL1, whereas the mycelial form is favored at
inoculum densities < 106mL1. Farnesoic acid (FA)
and farnesol (FOH) are two related sesquiterpene quo-
rum-sensing molecules (see Fig 1 for stuctures and
abbreviations) that, upon accumulation, prevent the
yeast-to-mycelial conversion. Oh et al. [2] showed that
C. albicans strain ATCC 10231 excretes FA, while
Hornby et al. [3] showed that C. albicans A72 and
SC5314 excrete FOH. Subsequent work indicated that
10231 was the only isolate of C. albicans that fails to
produce detectable FOH [4]. Moreover, when tested on
C. albicans A72, FA had only 3.2% of the hyphal-inhi-
bitory activity relative to FOH [5]. These observations
raised two questions: 1., Do FOH and FA block myce-
lial development via the same molecular mechanism;
and 2., What is the biochemical or physiologic differ-
ence in strain 10231 that underlies excretion of FA and
not FOH?
Do farnesol and farnesoic
acid share a common
mechanism of action?
This question has now been partially answered by Ahn
et al. [6], who explored how FA blocks mycelial devel-
opment of C. albicans SC5314. Previously, the same
authors had shown that CaPHO81, a key component
of the phosphate starvation response signal transduc-
tion pathway [7], is required for inhibition of hyphal
development by FA [8]. The pho81Δ mutant cells
existed exclusively as filaments and were insensitive to
inhibition by FA. In the current study, they have iden-
tified a previously unknown transcriptional activator
of PHO81, CaHot1p (orf 19.3328), which binds to the
PHO81 promoter region and induces the expression of
PHO81 in response to FA treatment. Similar to the
pho81Δ strain from their previous work, the hot1Δ
mutant cells grew exclusively as filaments and were
insensitive to FA inhibition of hyphal morphogenesis.
Most critically, two lines of evidence indicated that
FOH and FA, despite their close chemical similarity
(Fig. 1), use separate pathways to block hyphal devel-
opment. First, the hot1Δ mutant cells had lost their
sensitivity to FA but remained sensitive to FOH. Sec-
ond, the mRNA abundance of HOT1 and PHO81
increased dramatically between 40 and 240 min follow-
ing treatment with FA, but remained unchanged fol-
lowing treatment with FOH [6]. Indeed the study of
PH081 and HOT1 was driven in part by the previous
finding that these genes were among those induced in
C. albicans 10231 following the addition of FA [9].
This dichotomy between FOH and FA responses is
analogous to that described by Hall et al. [10] who
showed that FOH and 3-oxo-C12-homoserine lactone,
a quorum-sensing molecule secreted by Pseudomonas
aeruginosa, block hyphal development by a different
pathway from that used by the 12-carbon alcohol
dodecanol. Dodecanol exerted its effects through a
mechanism involving the C. albicans hyphal repressor
Sfl1p. Deletion of SFL1 did not affect the response to
FOH but did interfere with the response to dodecanol.
Importantly, Sfl1p can also be activated by the bacte-
rial signaling molecules DSF (cis-1-methyl-2-dodece-
noic acid) and BDSF (cis-2-dodecenoic acid), which
are structurally and functionally related to FA [11].
Our working hypothesis is that farnesoic acid aligns
with DSF and BDSF since they are all organic acids
with 12-carbon chain lengths.
Abbreviations
BDSF, cis-2-dodecenoic acid; DSF, cis-1-methyl-2-dodecenoic acid; FA, farnesoic acid; FOH, farnesol.
1637FEBS Letters 591 (2017) 1637–1640 ª 2017 Federation of European Biochemical Societies
An apparent paradox in the regulation
of hyphal morphogenesis by
CaPho81p
Phosphate starvation in fungi results in an induction of
high-affinity phosphate transporters, the secretion of
acid and alkaline phosphatases, and the reorganization
of cellular metabolism. This allows cells to acquire more
of, and to cope with the limitation of, this critical
macronutrient. Regulation of genes that are induced by
phosphate starvation is well characterized and essen-
tially conserved in ascomycetes such as C. albicans and
S. cerevisiae [7], and the core regulatory elements are
detailed in Fig. 2. Briefly, phosphate starvation-respon-
sive genes are under the control of the transcriptional
activator Pho4p, which is maintained in a hyperphos-
phorylated, inactive state by the action of the cyclin/cy-
clin-dependent kinase complex Pho85p/Pho80p.
Pho81p was identified as a cyclin-dependent kinase inhi-
bitor, and its activation by phosphate-limiting condi-
tions leads to a decrease in Pho80/Pho85 activity,
leading to dephosphorylation and activation of Pho4.
Recent work by Ikeh et al. [12] has identified CaPho4p
as an component of the fungal phosphate starvation
regulatory pathway that, like CaPho81p, also plays a
role in regulating hyphal morphogenesis. Pho4p is a
basic helix-loop-helix transcription factor that binds to
and activates genes involved with phosphate acquisition
and polyphosphate mobilization, and the work of Ikeh
et al. [12] showed that a pho4Δ mutant strain fails to
form hyphal germ tubes under hyphae-inducing condi-
tions. As noted above, in the context of phosphate star-
vation, the activity of Pho4p is regulated by its
phosphorylation status [7] as represented in Fig. 2. A
pho81Δ mutant strain would be expected to accumulate
hyperphosphorylated Pho4p, which is actively excluded
from the nucleus and thus inactive as a transcriptional
regulator. If we assume that it is the hypophosphory-
lated, nuclear-localized form of Pho4p that is active in
the regulation of filamentation, this raises a conflict with
the data presented by Chung et al. [8] and Ahn et al.
[6]. Specifically, a pho81Δ mutant strain would be
expected to favor the inactive form of Pho4p. This
assumption, by analogy to the filamentation defect
exhibited by the pho4Δ mutant presented in Ikeh et al.
[12], would lead us to expect that the pho81Δ mutant
(and by extension, the hot1Δ mutant) would fail to form
hyphae under favorable conditions. However, the oppo-
site outcome is demonstrated for these mutant strains,
with ectopic hyphal formation in conditions that nor-
mally favor the yeast form.
This apparent paradox can be explained by at least
two different models. First, it could be that the two
observations are not actually at odds if one assumes
that the hyperphosphorylated form of Pho4p is
responsible for hyphal induction via a mechanism that
is independent of its activity as a transcription factor.
This possibility seems unlikely, as it was shown
recently that phosphate starvation itself is a powerful
inducer of hyphal morphogenesis in a number of
highly virulent clinical isolates [13], suggesting that the
C. albicans Pho regulon is functionally linked to
hyphal induction, most likely via the Pho4p-mediated
mechanism presented in Fig. 2. An alternative and
perhaps more likely scenario is that Pho81p indeed
acts to regulate the phosphorylation status of Pho4p
by inhibiting the activity of the Pho80/Pho85 kinase
complex, but that it also acts as a negative regulator
of the hyphal induction pathway mediated by the Ras/
cAMP pathway. This seems more likely, as it has been
shown [8] that the pho81Δ strain accumulates an
abnormally high level of Ras-GTP, and that FA-
Fig. 1. Structures and biosynthesis of sequiterpene quorum-sensing molecules in C. albicans. The most likely explanation for FA production
by strain 10231 is the presence of an active farnesol and farnesal dehydrogenase pathway in this strain, and its absence from other clinical
isolates. The identities of these dehydrogenases are currently not defined.
1638 FEBS Letters 591 (2017) 1637–1640 ª 2017 Federation of European Biochemical Societies
Commentary
mediated inhibition of filamentation in a strain bearing
a hyperactive allele of Ras is dependent on the pres-
ence of Pho81p. Taken together, the evidence suggests
that Pho81p plays a positive role in regulating filamen-
tation via Pho4p activation, while playing a negative
role in filamentation by inhibition of the Ras/cAMP
pathway. This also suggests that under the conditions
operative in these studies, the Ras/cAMP pathway
plays a dominant role in the regulation of filamenta-
tion, and that the Pho4p-dependent filamentation
pathway plays a secondary role.
Why does C. albicans strain 10231
secrete farnesoic acid, while other
C. albicans strains secrete farnesol?
To the best of our knowledge and assessment of the
relevant literature, 10231 is the only strain of C. albi-
cans reported to secrete FA instead of FOH. Presum-
ably it makes FA from FOH through the pathway
that is also employed by insects and other inverte-
brates for the synthesis of juvenile hormone III, con-
verting FOH to farnesal via an alcohol dehydrogenase,
and then to FA via an aldehyde dehydrogenase
(Fig. 1). Strain 10231 was isolated in 1943 and has
been in the ATCC collection since 1965, although it
was used as a test organism for antifungal antibiotics
as early as 1956 [14]. It has at least nine alternate
strain designations and it is recommended for use in
the ASTM Standard Test Method E979-91. This rec-
ommendation is fitting because 10231 produces abun-
dant germ tubes [15] and chlamydospores [16] along
with forming especially black colonies on BiGGY
agar. Thus, it fulfills the three hallmarks for in vitro
diagnostic characterization of C. albicans.
However, in in vivo the virulence of strain 10231
may differ from that of other strains in a manner that
depends on FOH production [17, 18]. For instance,
Navarathna et al. [17] showed that FOH acted as a
virulence factor in a mouse model for candidiasis; a
mutant which produced six times less FOH was ca. 4.2
times less pathogenic than its parent. Similarly, the
LD50 dose for strain 10231 in a mouse model was
1.2 9 107 cells per mouse [17], a value six times higher
than the LD50 values for their FOH excreting counter-
parts [17]. Subsequently, Ghosh et al. [18] showed that
mouse macrophage cells produced ca. 1000 9 less IL-6
mRNA when challenged with strain 10231 than with a
series of FOH secreting of C. albicans. Strain 10231
elicited only background levels of IL-6 expression. The
RAW264.7 mouse macrophage cells produced more
IL-6, TLR2, and dectin1 mRNA by 100-, 2-, and 3-
fold, respectively, when exposed to a combination of
FOH and zymosan than a combination of FA and
zymosan [18]. More recently [19] we showed that FOH
stimulated the migration of mouse macrophages,
induced the rapid depletion of B cells from the mouse
peritoneal cavity, and recruited neutrophils, granulo-
cytes, and small peritoneal macrophages to the mouse
peritoneal cavity. Unfortunately, this study did not
include direct comparisons of FOH versus FA or of
C. albicans 10231 versus A72 or SC5314. Taken
together, these results strongly suggest that the altered
response of the innate immune system to strain 10231
relative to other isolates is due to differences in their
response to FOH versus FA. The genetic and bio-
chemical factors which contributed to the selection for
FA production versus FOH production are currently
undefined. However, their elucidation is likely to pro-
vide new details regarding the differences in virulence
Pho80/Pho85
Pho4P
P
P
PP
P
Pho81
Hot1
Hypophosphorylated: 
nuclear, active
Pho4
[IP7] [Pi][FA]
Transcriptional regulation of Pho81 Allosteric regulation of Pho81
Increased filamentous growth and phosphate uptake
Hyperphosphorylated:
cytoplasmic, inactive
Ras/cAMP mediated filamentous growth
Fig. 2. A model for the dual roles of Pho81 in inducing or suppressing pathways of filamentation. As described in the text, Pho81 negatively
regulates the Ras/cAMP-mediated pathway of hyphal morphogenesis, but likely plays a positive regulatory role in promoting hyphal
morphogenesis under phosphate-limiting conditions.
1639FEBS Letters 591 (2017) 1637–1640 ª 2017 Federation of European Biochemical Societies
Commentary
and immune responses between 10231 and other clini-
cal isolates of C. albicans.
References
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Nat Rev Microbiol 9, 737–748.
2 Oh KB, Miyazawa H, Naito T and Matsuoka H (2001)
Purification and characterization of an autoregulatory
substance capable of regulating the morphological
transition in Candida albicans. Proc Natl Acad Sci USA
98, 4664–4668.
3 Hornby JM, Jensen EC, Lisec AD, Tasto JJ, Jahnke B,
Shoemaker R, Dussault P and Nickerson KW (2001)
Quorum sensing in the dimorphic fungus Candida
albicans is mediated by farnesol. Appl Environ Microbiol
67, 2982–2992.
4 Hornby JM and Nickerson KW (2004) Enhanced
production of farnesol by Candida albicans treated with
four azoles. Antimicrob Agents Chemother 48, 2305–
2307.
5 Shchepin R, Hornby JM, Burger E, Niessen T,
Dussault P and Nickerson KW (2003) Quorum sensing
in Candida albicans: probing farnesol’s mode of action
with 40 natural and synthetic farnesol analogs. Chem
Biol 10, 743–750.
6 Ahn CH, Lee S, Cho E, Kim H, Park W and Oh KB
(2017) A farnesoic acid-responsive transcription factor,
Hot1, that regulates yeast-hypha morphogenesis in
Candida albicans. FEBS Lett 591, 1225–1235.
7 Tomar P and Sinha H (2014) Conservation of PHO
pathway in ascomycetes and the role of Pho84. J Biosci
39, 1–12.
8 Chung SC, Kim TI, Ahn CH, Shin J and Oh KB (2010)
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of hyphal development by farnesoic acid. FEBS Lett
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9 Chung SC, Lee JY and Oh KB (2005) cDNA cloning of
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L, Sanglard D, Levin LR, Buck J and M€uhlschlegel FA
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CM, Tarrant E, Waldron KJ, Banks AP, Bain JM,
Lydall D, Veal EA et al. (2016) Pho4 mediates
phosphate acquisition in Candida albicans and is vital
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13 Romanowski K, Zaborin A, Valuckaite V, Rolfes RJ,
Babrowski T, Bethel C, Olivas A, Zaborina O and
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phenotype. PLoS ONE 7, e30119.
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1640 FEBS Letters 591 (2017) 1637–1640 ª 2017 Federation of European Biochemical Societies
Commentary


Quorum sensing in \u3ci\u3eCandida albicans\u3c/i\u3e: farnesol versus
farnesoic acid

DigitalCommons@University of Nebraska

University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Kenneth Nickerson Papers Papers in the Biological Sciences 2017 Quorum sensing in Candida albicans: farnesol versus farnesoic acid Wayne R. Riekhof Kenneth Nickerson Follow this and additional works at: https://digitalcommons.unl.edu/bioscinickerson  Part of the Environmental Microbiology and Microbial Ecology Commons, Other Life Sciences Commons, and the Pathogenic Microbiology Commons This Article is brought to you for free and open access by the Papers in the Biological Sciences at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Kenneth Nickerson Papers by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. COMMENTARYQuorum sensing in Candida albicans: farnesol versusfarnesoic acidWayne R. Riekhof and Kenneth W. NickersonSchool of Biological Sciences, University of Nebraska – Lincoln, Lincoln, NE, USACandida albicans is a clinically important dimorphicfungus that exhibits either a budding yeast or a myce-lial-hyphal or pseudohyphal growth, depending onenvironmental conditions. The yeast-to-mycelia mor-phologic transition, which is generally regarded as animportant virulence determinant [1], depends on theinoculum size of liquid cultures. The yeast form isfavored when cultures are inoculated at > 106cellsmL1, whereas the mycelial form is favored atinoculum densities < 106mL1. Farnesoic acid (FA)and farnesol (FOH) are two related sesquiterpene quo-rum-sensing molecules (see Fig 1 for stuctures andabbreviations) that, upon accumulation, prevent theyeast-to-mycelial conversion. Oh et al. [2] showed thatC. albicans strain ATCC 10231 excretes FA, whileHornby et al. [3] showed that C. albicans A72 andSC5314 excrete FOH. Subsequent work indicated that10231 was the only isolate of C. albicans that fails toproduce detectable FOH [4]. Moreover, when tested onC. albicans A72, FA had only 3.2% of the hyphal-inhi-bitory activity relative to FOH [5]. These observationsraised two questions: 1., Do FOH and FA block myce-lial development via the same molecular mechanism;and 2., What is the biochemical or physiologic differ-ence in strain 10231 that underlies excretion of FA andnot FOH?Do farnesol and farnesoicacid share a commonmechanism of action?This question has now been partially answered by Ahnet al. [6], who explored how FA blocks mycelial devel-opment of C. albicans SC5314. Previously, the sameauthors had shown that CaPHO81, a key componentof the phosphate starvation response signal transduc-tion pathway [7], is required for inhibition of hyphaldevelopment by FA [8]. The pho81Δ mutant cellsexisted exclusively as filaments and were insensitive toinhibition by FA. In the current study, they have iden-tified a previously unknown transcriptional activatorof PHO81, CaHot1p (orf 19.3328), which binds to thePHO81 promoter region and induces the expression ofPHO81 in response to FA treatment. Similar to thepho81Δ strain from their previous work, the hot1Δmutant cells grew exclusively as filaments and wereinsensitive to FA inhibition of hyphal morphogenesis.Most critically, two lines of evidence indicated thatFOH and FA, despite their close chemical similarity(Fig. 1), use separate pathways to block hyphal devel-opment. First, the hot1Δ mutant cells had lost theirsensitivity to FA but remained sensitive to FOH. Sec-ond, the mRNA abundance of HOT1 and PHO81increased dramatically between 40 and 240 min follow-ing treatment with FA, but remained unchanged fol-lowing treatment with FOH [6]. Indeed the study ofPH081 and HOT1 was driven in part by the previousfinding that these genes were among those induced inC. albicans 10231 following the addition of FA [9].This dichotomy between FOH and FA responses isanalogous to that described by Hall et al. [10] whoshowed that FOH and 3-oxo-C12-homoserine lactone,a quorum-sensing molecule secreted by Pseudomonasaeruginosa, block hyphal development by a differentpathway from that used by the 12-carbon alcoholdodecanol. Dodecanol exerted its effects through amechanism involving the C. albicans hyphal repressorSfl1p. Deletion of SFL1 did not affect the response toFOH but did interfere with the response to dodecanol.Importantly, Sfl1p can also be activated by the bacte-rial signaling molecules DSF (cis-1-methyl-2-dodece-noic acid) and BDSF (cis-2-dodecenoic acid), whichare structurally and functionally related to FA [11].Our working hypothesis is that farnesoic acid alignswith DSF and BDSF since they are all organic acidswith 12-carbon chain lengths.AbbreviationsBDSF, cis-2-dodecenoic acid; DSF, cis-1-methyl-2-dodecenoic acid; FA, farnesoic acid; FOH, farnesol.1637FEBS Letters 591 (2017) 1637–1640 ª 2017 Federation of European Biochemical SocietiesAn apparent paradox in the regulationof hyphal morphogenesis byCaPho81pPhosphate starvation in fungi results in an induction ofhigh-affinity phosphate transporters, the secretion ofacid and alkaline phosphatases, and the reorganizationof cellular metabolism. This allows cells to acquire moreof, and to cope with the limitation of, this criticalmacronutrient. Regulation of genes that are induced byphosphate starvation is well characterized and essen-tially conserved in ascomycetes such as C. albicans andS. cerevisiae [7], and the core regulatory elements aredetailed in Fig. 2. Briefly, phosphate starvation-respon-sive genes are under the control of the transcriptionalactivator Pho4p, which is maintained in a hyperphos-phorylated, inactive state by the action of the cyclin/cy-clin-dependent kinase complex Pho85p/Pho80p.Pho81p was identified as a cyclin-dependent kinase inhi-bitor, and its activation by phosphate-limiting condi-tions leads to a decrease in Pho80/Pho85 activity,leading to dephosphorylation and activation of Pho4.Recent work by Ikeh et al. [12] has identified CaPho4pas an component of the fungal phosphate starvationregulatory pathway that, like CaPho81p, also plays arole in regulating hyphal morphogenesis. Pho4p is abasic helix-loop-helix transcription factor that binds toand activates genes involved with phosphate acquisitionand polyphosphate mobilization, and the work of Ikehet al. [12] showed that a pho4Δ mutant strain fails toform hyphal germ tubes under hyphae-inducing condi-tions. As noted above, in the context of phosphate star-vation, the activity of Pho4p is regulated by itsphosphorylation status [7] as represented in Fig. 2. Apho81Δ mutant strain would be expected to accumulatehyperphosphorylated Pho4p, which is actively excludedfrom the nucleus and thus inactive as a transcriptionalregulator. If we assume that it is the hypophosphory-lated, nuclear-localized form of Pho4p that is active inthe regulation of filamentation, this raises a conflict withthe data presented by Chung et al. [8] and Ahn et al.[6]. Specifically, a pho81Δ mutant strain would beexpected to favor the inactive form of Pho4p. Thisassumption, by analogy to the filamentation defectexhibited by the pho4Δ mutant presented in Ikeh et al.[12], would lead us to expect that the pho81Δ mutant(and by extension, the hot1Δ mutant) would fail to formhyphae under favorable conditions. However, the oppo-site outcome is demonstrated for these mutant strains,with ectopic hyphal formation in conditions that nor-mally favor the yeast form.This apparent paradox can be explained by at leasttwo different models. First, it could be that the twoobservations are not actually at odds if one assumesthat the hyperphosphorylated form of Pho4p isresponsible for hyphal induction via a mechanism thatis independent of its activity as a transcription factor.This possibility seems unlikely, as it was shownrecently that phosphate starvation itself is a powerfulinducer of hyphal morphogenesis in a number ofhighly virulent clinical isolates [13], suggesting that theC. albicans Pho regulon is functionally linked tohyphal induction, most likely via the Pho4p-mediatedmechanism presented in Fig. 2. An alternative andperhaps more likely scenario is that Pho81p indeedacts to regulate the phosphorylation status of Pho4pby inhibiting the activity of the Pho80/Pho85 kinasecomplex, but that it also acts as a negative regulatorof the hyphal induction pathway mediated by the Ras/cAMP pathway. This seems more likely, as it has beenshown [8] that the pho81Δ strain accumulates anabnormally high level of Ras-GTP, and that FA-Fig. 1. Structures and biosynthesis of sequiterpene quorum-sensing molecules in C. albicans. The most likely explanation for FA productionby strain 10231 is the presence of an active farnesol and farnesal dehydrogenase pathway in this strain, and its absence from other clinicalisolates. The identities of these dehydrogenases are currently not defined.1638 FEBS Letters 591 (2017) 1637–1640 ª 2017 Federation of European Biochemical SocietiesCommentarymediated inhibition of filamentation in a strain bearinga hyperactive allele of Ras is dependent on the pres-ence of Pho81p. Taken together, the evidence suggeststhat Pho81p plays a positive role in regulating filamen-tation via Pho4p activation, while playing a negativerole in filamentation by inhibition of the Ras/cAMPpathway. This also suggests that under the conditionsoperative in these studies, the Ras/cAMP pathwayplays a dominant role in the regulation of filamenta-tion, and that the Pho4p-dependent filamentationpathway plays a secondary role.Why does C. albicans strain 10231secrete farnesoic acid, while otherC. albicans strains secrete farnesol?To the best of our knowledge and assessment of therelevant literature, 10231 is the only strain of C. albi-cans reported to secrete FA instead of FOH. Presum-ably it makes FA from FOH through the pathwaythat is also employed by insects and other inverte-brates for the synthesis of juvenile hormone III, con-verting FOH to farnesal via an alcohol dehydrogenase,and then to FA via an aldehyde dehydrogenase(Fig. 1). Strain 10231 was isolated in 1943 and hasbeen in the ATCC collection since 1965, although itwas used as a test organism for antifungal antibioticsas early as 1956 [14]. It has at least nine alternatestrain designations and it is recommended for use inthe ASTM Standard Test Method E979-91. This rec-ommendation is fitting because 10231 produces abun-dant germ tubes [15] and chlamydospores [16] alongwith forming especially black colonies on BiGGYagar. Thus, it fulfills the three hallmarks for in vitrodiagnostic characterization of C. albicans.However, in in vivo the virulence of strain 10231may differ from that of other strains in a manner thatdepends on FOH production [17, 18]. For instance,Navarathna et al. [17] showed that FOH acted as avirulence factor in a mouse model for candidiasis; amutant which produced six times less FOH was ca. 4.2times less pathogenic than its parent. Similarly, theLD50 dose for strain 10231 in a mouse model was1.2 9 107 cells per mouse [17], a value six times higherthan the LD50 values for their FOH excreting counter-parts [17]. Subsequently, Ghosh et al. [18] showed thatmouse macrophage cells produced ca. 1000 9 less IL-6mRNA when challenged with strain 10231 than with aseries of FOH secreting of C. albicans. Strain 10231elicited only background levels of IL-6 expression. TheRAW264.7 mouse macrophage cells produced moreIL-6, TLR2, and dectin1 mRNA by 100-, 2-, and 3-fold, respectively, when exposed to a combination ofFOH and zymosan than a combination of FA andzymosan [18]. More recently [19] we showed that FOHstimulated the migration of mouse macrophages,induced the rapid depletion of B cells from the mouseperitoneal cavity, and recruited neutrophils, granulo-cytes, and small peritoneal macrophages to the mouseperitoneal cavity. Unfortunately, this study did notinclude direct comparisons of FOH versus FA or ofC. albicans 10231 versus A72 or SC5314. Takentogether, these results strongly suggest that the alteredresponse of the innate immune system to strain 10231relative to other isolates is due to differences in theirresponse to FOH versus FA. The genetic and bio-chemical factors which contributed to the selection forFA production versus FOH production are currentlyundefined. However, their elucidation is likely to pro-vide new details regarding the differences in virulencePho80/Pho85Pho4PPPPPPPho81Hot1Hypophosphorylated: nuclear, activePho4[IP7] [Pi][FA]Transcriptional regulation of Pho81 Allosteric regulation of Pho81Increased filamentous growth and phosphate uptakeHyperphosphorylated:cytoplasmic, inactiveRas/cAMP mediated filamentous growthFig. 2. A model for the dual roles of Pho81 in inducing or suppressing pathways of filamentation. As described in the text, Pho81 negativelyregulates the Ras/cAMP-mediated pathway of hyphal morphogenesis, but likely plays a positive regulatory role in promoting hyphalmorphogenesis under phosphate-limiting conditions.1639FEBS Letters 591 (2017) 1637–1640 ª 2017 Federation of European Biochemical SocietiesCommentaryand immune responses between 10231 and other clini-cal isolates of C. albicans.References1 Sudbery PE (2011) Growth of Candida albicans hyphae.Nat Rev Microbiol 9, 737–748.2 Oh KB, Miyazawa H, Naito T and Matsuoka H (2001)Purification and characterization of an autoregulatorysubstance capable of regulating the morphologicaltransition in Candida albicans. Proc Natl Acad Sci USA98, 4664–4668.3 Hornby JM, Jensen EC, Lisec AD, Tasto JJ, Jahnke B,Shoemaker R, Dussault P and Nickerson KW (2001)Quorum sensing in the dimorphic fungus Candidaalbicans is mediated by farnesol. Appl Environ Microbiol67, 2982–2992.4 Hornby JM and Nickerson KW (2004) Enhancedproduction of farnesol by Candida albicans treated withfour azoles. Antimicrob Agents Chemother 48, 2305–2307.5 Shchepin R, Hornby JM, Burger E, Niessen T,Dussault P and Nickerson KW (2003) Quorum sensingin Candida albicans: probing farnesol’s mode of actionwith 40 natural and synthetic farnesol analogs. ChemBiol 10, 743–750.6 Ahn CH, Lee S, Cho E, Kim H, Park W and Oh KB(2017) A farnesoic acid-responsive transcription factor,Hot1, that regulates yeast-hypha morphogenesis inCandida albicans. FEBS Lett 591, 1225–1235.7 Tomar P and Sinha H (2014) Conservation of PHOpathway in ascomycetes and the role of Pho84. J Biosci39, 1–12.8 Chung SC, Kim TI, Ahn CH, Shin J and Oh KB (2010)Candida albicans PHO81 is required for the inhibitionof hyphal development by farnesoic acid. FEBS Lett584, 4639–4645.9 Chung SC, Lee JY and Oh KB (2005) cDNA cloning offarnesoic acid-induced genes in Candida albicans bydifferential display analysis. J Microbiol Biotechnol 15,1146–1151.10 Hall RA, Turner KJ, Chaloupka J, Cottier F, DeSordiL, Sanglard D, Levin LR, Buck J and M€uhlschlegel FA(2011) The quorum sensing molecules farnesol/homoserine lactone and dodecanol operate via distinctmodes of action in Candida albicans. Eukaryot Cell 10,1034–1042.11 Wang LH, He Y, Gao Y, Wu JE, Dong YH, He C,Wang SX, Weng LX, Xu JL, Tay L et al. (2004) Abacterial cell-cell communication signal with cross-kingdom structural analogues. Mol Microbiol 51, 903–912.12 Ikeh MAC, Kastora SL, Day AM, Herrero-de-DiosCM, Tarrant E, Waldron KJ, Banks AP, Bain JM,Lydall D, Veal EA et al. (2016) Pho4 mediatesphosphate acquisition in Candida albicans and is vitalfor stress resistance and metal homeostasis. Mol BiolCell 27, 2784–2801.13 Romanowski K, Zaborin A, Valuckaite V, Rolfes RJ,Babrowski T, Bethel C, Olivas A, Zaborina O andAlverdy JC (2012) Candida albicans isolates from thegut of critically ill patients respond to phosphatelimitation by expressing filaments and a lethalphenotype. PLoS ONE 7, e30119.14 Taber WA (1956) An agar diffusion assay method forthe antifungal polyene, candidin. Can J Microbiol 2,45–55.15 Kim D, Shin WS, Lee KH, Kim K, Park JY and KohCM (2002) Rapid differentiation of Candida albicansfrom other Candida species using its unique germ tubeformation at 39°C. Yeast 19, 957–962.16 Montazeri M and Hedrick HG (1984) Factors affectingspore formation of a Candida albicans strain. ApplEnviron Microbiol 47, 1341–1342.17 Navarathna DHMLP, Hornby JM, Krishnan N,Parkhurst A, Duhamel GE and Nickerson KW (2007)Effect of farnesol on a mouse model of systemiccandidiasis, determined by use of a DPP3 knockoutmutant of Candida albicans. Infect Immun 75, 1609–1618.18 Ghosh S, Howe N, Volk K, Tati S, Nickerson KW andPetro TM (2010) Candida albicans cell wall componentsand farnesol stimulate the expression of bothinflammatory and regulatory cytokines in the murineRAW264.7 macrophage cell line. FEMS Immunol MedMicrobiol 60, 63–73.19 Hargarten JC, Moore TC, Petro TM, Nickerson KWand Atkin AL (2015) Candida albicans quorum sensingmolecules stimulate mouse macrophage migration.Infect Immun 83, 3857–3864.1640 FEBS Letters 591 (2017) 1637–1640 ª 2017 Federation of European Biochemical SocietiesCommentary

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Quorum sensing in \u3ci\u3eCandida albicans\u3c/i\u3e: farnesol versus farnesoic acid

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