Faculty Opinions recommendation of White-opaque switching in Candida albicans is controlled by mating-type locus homeodomain proteins and allows efficient mating.

ABSTRACT Recently, evidence was presented that in a collection of fluconazole-resistant strains of Candida albicans there was a much higher proportion of homozygotes for the mating type locus (MTL) than in a collection of fluconazole-sensitive isolates, suggesting the possibility that when cells become MTL homozygous they acquire intrinsic drug resistance. To investigate this possibility, an opposite strategy was employed. First, drug susceptibility was measured in a collection of isolates selected for MTL homozygosity. The majority of these isolates had not been exposed to antifungal drugs. Second, the level of drug susceptibility was compared between spontaneously generated MTL-homozygous progeny and their MTL-heterozygous parent strains which had not been exposed to antifungal drugs. The results demonstrate that naturally occurring MTL-homozygous strains are not intrinsically more drug resistant, supporting the hypotheses that either the higher incidence of MTL homozygosity previously demonstrated among fluconazole-resistant isolates involved associated homozygosity of a drug resistance gene linked to the MTL locus, or that MTL-homozygous strains may be better at developing drug resistance upon exposure to the drug than MTL-heterozygous strains. Furthermore, the results demonstrate that a switch by an MTL-homozygous strain from the white to opaque phenotype, the latter functioning as the facilitator of mating, does not notably alter drug susceptibility.

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Deletion of a Yci1 Domain Protein ofCandida albicansAllows Homothallic Mating inMTLHeterozygous Cells

mBio ◽

10.1128/mbio.00465-16 ◽

2016 ◽

Vol 7 (2) ◽

Cited By ~ 5

Author(s):

Yuan Sun ◽

Christine Gadoury ◽

Matthew P. Hirakawa ◽

Richard J. Bennett ◽

Doreen Harcus ◽

...

Keyword(s):

Candida Albicans ◽

Mating Type ◽

Transcriptional Profiling ◽

Mammalian Host ◽

Epigenetic Switch ◽

Type Locus ◽

Human Fungal Pathogen ◽

Mating Type Locus ◽

New Gene

ABSTRACTIt has been proposed that the ancestral fungus was mating competent and homothallic. However, many mating-competent fungi were initially classified as asexual because their mating capacity was hidden behind layers of regulation. For efficientin vitromating, the essentially obligate diploid ascomycete pathogenCandida albicanshas to change its mating type locus from heterozygousMTLa/α to homozygousMTLa/aorMTLα/α and then undergo an environmentally controlled epigenetic switch to the mating-competent opaque form. These requirements greatly reduce the potential forC. albicansmating. Deletion of the Yci1 domain geneOFR1bypasses the need forC. albicanscells to change the mating type locus from heterozygous to homozygous prior to switching to the opaque form and mating and allows homothallic mating ofMTLheterozygous strains. This bypass is carbon source dependent and does not occur when cells are grown on glucose. Transcriptional profiling ofofr1mutant cells shows that in addition to regulating cell type and mating circuitry, Ofr1 is needed for proper regulation of histone and chitin biosynthesis gene expression. It appears thatOFR1is a key regulator inC. albicansand functions in part to maintain the cryptic mating phenotype of the pathogen.IMPORTANCECandida albicansis a human fungal pathogen with a recently discovered, highly cryptic mating ability. For efficient mating, it has to lose heterozygosity at its mating type locus. Then,MTLhomozygous strains can undergo an epigenetic switch to an elongated yeast state, termed the opaque form, and become mating competent. This infrequent two-step process greatly reduces the potential for mating; few strains areMTLhomozygous, and the opaque state is unstable at the temperature of the mammalian host.C. albicanshas a complex mechanism for mating that appears designed to ensure that mating is infrequent. Here, we have characterized a new gene, opaque-formation regulator 1 (OFR1). Deleting theOFR1gene allowsMTLa/α strains to mate efficiently with either mating type or even mate homothallically. It is possible that downregulatingOFR1in the host environment could allow mating inC. albicansby a route that does not involveMTLhomozygosis.

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The Mating-Type Locus and Mating of Candida albicans and Candida glabrata

Molecular Principles of Fungal Pathogenesis ◽

10.1128/9781555815776.ch7 ◽

2014 ◽

pp. 89-112 ◽

Cited By ~ 1

Author(s):

David R. Soll

Keyword(s):

Candida Albicans ◽

Mating Type ◽

Candida Glabrata ◽

Type Locus ◽

Mating Type Locus

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The [URE3] Prion in Candida

Eukaryotic Cell ◽

10.1128/ec.00015-13 ◽

2013 ◽

Vol 12 (4) ◽

pp. 551-558 ◽

Cited By ~ 15

Author(s):

Herman K. Edskes ◽

Reed B. Wickner

Keyword(s):

Saccharomyces Cerevisiae ◽

Candida Albicans ◽

Mating Type ◽

Test Bed ◽

Type Locus ◽

Content Type ◽

Mating Type Locus ◽

Domain Sequence

ABSTRACTUre2p, normally a regulator of nitrogen catabolism inSaccharomyces cerevisiae, can be a prion (infectious protein) by forming a folded in-register parallel amyloid called [URE3]. UsingS. cerevisiaeas a test bed, we previously showed that Ure2p ofCandida albicans(CaUre2p) can also form a prion, but that Ure2p ofC. glabrata(CgUre2p) cannot. Here, we constructedC. glabratastrains to test whether CgUre2p can form a prion in its native environment. We find that while CaUre2p can form a [URE3] inC. glabrata, CgUre2p cannot, although the latter has a prion domain sequence more similar to that of ScUre2p than that of CaUre2p. This supports the notion that prion formation is not a conserved property of Ure2p but is a pathology arising sporadically. We find that some [URE3albicans] variants are restricted in their transmissibility to certain recipient strains. In addition, we show that theC. glabrataHO can induce switching of theC. glabratamating type locus.

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In Candida albicans, White-Opaque Switchers Are Homozygous for Mating Type

Genetics ◽

10.1093/genetics/162.2.737 ◽

2002 ◽

Vol 162 (2) ◽

pp. 737-745 ◽

Cited By ~ 2

Author(s):

Shawn R Lockhart ◽

Claude Pujol ◽

Karla J Daniels ◽

Matthew G Miller ◽

Alexander D Johnson ◽

...

Keyword(s):

Candida Albicans ◽

Mating Type ◽

High Frequency ◽

Fungal Pathogen ◽

Clinical Isolates ◽

Very High Frequency ◽

Type Locus ◽

Mating Type Locus ◽

The Relationship ◽

Very High

Abstract The relationship between the configuration of the mating type locus (MTL) and white-opaque switching in Candida albicans has been examined. Seven genetically unrelated clinical isolates selected for their capacity to undergo the white-opaque transition all proved to be homozygous at the MTL locus, either MTLa or MTLα. In an analysis of the allelism of 220 clinical isolates representing the five major clades of C. albicans, 3.2% were homozygous and 96.8% were heterozygous at the MTL locus. Of the seven identified MTL homozygotes, five underwent the white-opaque transition. Of 20 randomly selected MTL heterozygotes, 18 did not undergo the white-opaque transition. The two that did were found to become MTL homozygous at very high frequency before undergoing white-opaque switching. Our results demonstrate that only MTL homozygotes undergo the white-opaque transition, that MTL heterozygotes that become homozygous at high frequency exist, and that the generation of MTL homozygotes and the white-opaque transition occur in isolates in different genetic clades of C. albicans. Our results demonstrate that mating-competent strains of C. albicans exist naturally in patient populations and suggest that mating may play a role in the genesis of diversity in this pernicious fungal pathogen.

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