Environmental sensing and signal transduction pathways regulating morphopathogenic determinants of Candida albicans

Abstract

Candida albicans is an opportunistic fungal pathogen that is found in the normal gastrointestinal flora of most healthy humans. However, under certain environmental conditions, it can become a life-threatening pathogen. The shift from commensal organism to pathogen is often correlated with the capacity to undergo morphogenesis. Indeed, under certain conditions, including growth at ambient temperature, the presence of serum or N-acetylglucosamine, neutral pH, and nutrient starvation, C. albicans can undergo reversible transitions from the yeast form to the mycelial form. This morphological plasticity reflects the interplay of various signal transduction pathways, either stimulating or repressing hyphal formation. In this review, we provide an overview of the different sensing and signaling pathways involved in the morphogenesis and pathogenesis of C. albicans. Where appropriate, we compare the analogous pathways/genes in Saccharomyces cerevisiae in an attempt to highlight the evolution of the different components of the two organisms. The downstream components of these pathways, some of which may be interesting antifungal targets, are also discussed.

FIG. 1.

Regulation of dimorphism in C. albicans by multiple signaling pathways. The Cph1-mediated MAPK pathway and the Efg1-mediated cAMP pathway are well-characterized signaling pathways in dimorphic regulation. In C. albicans, Ras1 is an important regulator of hyphal development and likely functions upstream of both pathways. In the cAMP-PKA pathway, two catalytic subunits or isoforms of PKA, Tpk1 and Tpk2, have differential effects on hyphal morphogenesis under different hypha-inducing conditions. The MAPK cascade includes Cst20 (PAK), Hst7 (MAPKK), Cek1 (MAPK), and the downstream transcription factor Cph1, which is a homolog of the S. cerevisiae transcription factor Ste12. Transcription of the hyphal regulator TEC1 is regulated by Efg1 and Cph2. Rim101 or Czf1 may function through Efg1 or act in parallel with Efg1. Tup1 is the negative regulator of the hyphal transition. Tup1, recruited by Rfg1, Nrg1, or Mig1, and Rbf1 are also implicated in dimorphic transitions. GlcNAc-inducible hexokinase, Hxk1, plays a negative role in hyphal development under certain conditions. Cell wall proteins (HWP1 and ECE1, etc., which are involved in adherence) are also regulated by Efg1. Transcription factors are shown in rectangular boxes.

FIG. 2.

(Top) White-opaque switching in C. albicans. Shown are scanning electron micrographs at a magnification of ×1,000 and bright-field images of white and opaque cells. (Reprinted, with permission, from the Annual Review of Microbiology [26], volume 59, © 2005 by Annual Reviews.) (Bottom) Model of morphogenetic regulation by Efg1. Under hypha-inducing conditions (e.g., serum, GlcNAc), Efg1 is induced and activated; under microaerophilic conditions, however, it is repressed. The activated Efg1 (by PKA isoforms Tpk1 and Tpk2) initiates hyphal formation by inducing genes involved in hyphal formation and/or repressing genes directing the yeast form. Efg1 also induces the cell wall proteins (HWP1, HWP2, and RBE1) that are involved in adherence. The phase-specific genes (at the white-to-opaque-phase transition period) are also induced by Efg1. In parallel, Efg1, in conjunction with the Sin3-Rpd3 deacetylase complex, silences chromatin and thereby down-regulates EFG1 promoter activity (294). The 3.2-kb major transcript of EFG1 is expressed in the white phase, and the less-abundant 2.2-kb transcript is expressed in opaque cells. The Hda1-Rpd3 deacetylase complex regulates the white-to-opaque-phase transition as well as EFG1 down-regulation (279).

FIG. 3.

Multiple environmental conditions activate the kinase cascade, resulting in coordination of the stress response with morphogenesis. Arrows indicate activation; lines with bars indicate inhibition. See the text for details.

FIG. 4.

(Top) Ssn6 is not directly required for Tup1-mediated repression of hypha-specific genes (HSG's), and Tup1 may interact directly with the DBP. The DBP-responsive element (RE) may affect Ssn6 dependency. (Bottom) Model summarizing the transcriptional repression mediated by Tup1, Nrg1, Mig1, and Rfg1 in C. albicans.

FIG. 5.

Downstream targets of the PKC pathway. Under environmental stress conditions, the MAPK Mkc1 is activated in a Pck1-dependent manner. Then, it activates transcription factors Efg1, Czf1, and Bcr1 under different conditions for morphogenesis in C. albicans. CZF1 expression requires Efg1 and is negatively regulated by Czf1. Tec1 regulates the expression of BCR1.

FIG. 6.

(Top) Chromosomal organization of the NAG gene cluster in C. albicans. The organization of the cluster of genes on chromosome 6 and their direction of transcription are illustrated. NAG1 and DAC1 are transcribed in opposite directions from a bidirectional promoter. (Bottom) Metabolism of GlcNAc in C. albicans. GlcNAc is synthesized by C. albicans from fructose-6-phosphate by sequential action of glutamine: Frc 6-P amidotransferase (Gfp1), GlcN6-P acetyltransferase (Gna1), GlcNAc6P mutase (Agm1), UDP-GlcNAc pyrophosphorylase (Uap1). On the other hand, GlcNAc permease, GlcNAc kinase, GlcNAc-6-phosphate deacetylase, and GlcN-6-phosphate deaminase act sequentially on GlcNAc to generate the fructose-6-phosphate that is fed into the glycolytic pathway. N-Acetylmannosamine epimerase converts N-acetylmannosamine, which is imported in the cell by an unknown permease (?), into GlcNAc. Glucosamine can directly enter the cell via a general sugar permease and is converted to glucosamine-6-phosphate by the action of a GlcN-kinase.

FIG. 7.

Alkaline responses in Rim101 regulation. Alkaline pH stimulates Rim101 activity through increased expression and proteolytic activation. The ESCRT-I, ESCRT-II, and Snf7-Vps20 complexes are required for Rim101 activation. The Rim13p-dependent C-terminal proteolytic processing event also depends on Rim20, Rim8, and other transmembrane proteins. Full-length Rim101-long does not have a known activity. Processed Rim101-short is required for the alkaline response, which includes activation of alkaline pH-induced genes, repression of alkaline pH-repressed genes, and filamentation. Since Rim101 is an alkaline pH-induced gene, its expression may depend on autoregulation by Rim101-short. Alkaline pH also stimulates a RIM101-independent pathway. This pathway activates PHR2 expression and stimulates filamentation in conjugation with Rim101.

FIG. 8.

Transcriptional and functional regulation of HWP1. Transcription of HWP1 is regulated by Efg1. Interestingly, the hyphal gene repressors Tup1 and Rbf1 are positive regulators of Hwp1, whereas the MADS box transcription factor Mcm1 (245) negatively regulates HWP1 transcription. The pH regulators Mds3 and Dfg5 are required for expression of HWP1 in alkaline medium (74). HWP1 is expressed in conjugation tubes of a/a cells by α pheromone of opposite-mating-type cells (184). The cell surface protein Hwp1 is involved in adherence and plays a role in mating.