Candida albicans is a common cause of mucosal infections. In certain groups of immunocompromised patients it also causes life-threatening bloodstream infections that are disseminated to internal organs. It is a polymorphic fungus, being able to grow in yeast, hyphal and pseudohyphal forms. The hyphal form penetrates epithelia and endothelia, causing tissue damage and allowing access to the bloodstream.
C. albicans is exquisitely sensitive to the multiple environments that it encounters in the human host and forms hyphae in response to cues such as 37 °C temperature, serum, CO2 and O2 tension, and neutral pH. The morphological switch is also regulated by the presence of not only other C. albicans cells but also bacterial cells, both of which are sensed through quorum sensing compounds.
Environmental signals are transduced through multiple pathways that target multiple transcription factors, resulting in the expression of a panel of hypha-specific genes. A key pathway is based on cyclic AMP and targets the transcription factor enhanced filamentous growth protein (Efg1). In this pathway, adenylyl cyclase, which is encoded by CYR1, integrates multiple cues in Ras-dependent and Ras-independent ways. Negative regulation is exerted by the general transcriptional corepressor Tup1, which is targeted to hypha-specific genes by the DNA-binding proteins Nrg1 and Rox1p-like regulator of filamentous growth (Rfg1).
The key outputs of the signal transduction pathway are the expression of three genes, UME6, EED1 and hyphal G1 cyclin protein 1 (HGC1). Overexpression of the transcription factor Ume6 forces ectopic hyphal growth. The role of Eed1 is currently unclear, but current research suggests that it lies upstream of Ume6. Hgc1 is the C. albicans homologue of the S. cerevisiae Ccn1 and Cln2 G1 cyclin pair, which activate the cyclin-dependent kinase cell division control 28 (Cdc28).
Hyphae grow in a highly polarized manner from their tip. This requires the delivery of secretory vesicles along actin cables. These vesicles accumulate in a subapical region called the Spitzenkörper before they fuse with the plasma membrane at the tip after docking with a multiprotein structure called the exocyst.
Cell separation after cytokinesis is suppressed in hyphae. This suppression involves phosphorylation of Efg1, which then associates with the promoters of genes encoding septum-degrading enzymes, repressing their Ace2-mediated transcription. A second mechanism suppressing cell separation involves the exclusion of the Cdc14 phosphatase from the septin ring, the subunits of which have different dynamic properties in yeast and hyphae.
A key role for kinases is emerging in the cell biology of hyphal growth. Hgc1–Cdc28 targets Rga2, Sec2 and Mob2, as well as Efg1. Rga2 is a GTPase-activating protein (GAP) that negatively regulates the GTPase Cdc42, which has a central role in orchestrating polarized growth. Sec2 is the guanosine exchange factor (GEF) that activates the GTPase Sec4, which is required for polarized exocytosis. Mob2 is the activating partner of the kinase Cbk1, which is absolutely required for hyphal growth. Upon hyphal induction, Cdc28 is partnered by a different cyclin, Ccn1, and cooperates with another kinase, growth-inhibitory protein 4 (Gin4), to phosphorylate the septin Cdc11.
The fungus Candida albicans is often a benign member of the mucosal flora; however, it commonly causes mucosal disease with substantial morbidity and in vulnerable patients it causes life-threatening bloodstream infections. A striking feature of its biology is its ability to grow in yeast, pseudohyphal and hyphal forms. The hyphal form has an important role in causing disease by invading epithelial cells and causing tissue damage. This Review describes our current understanding of the network of signal transduction pathways that monitors environmental cues to activate a programme of hypha-specific gene transcription, and the molecular processes that drive the highly polarized growth of hyphae.
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Work in the author's laboratory is supported by the UK Biotechnology and Biological Sciences Research Council grant BB-F007892.
The author declares no competing financial interests.
List of hyphal induced genes. (PDF 107 kb)
Continuous presence of the Spitzenkörper at the hyphal tip. (MPG 12901 kb)
Secretory vesicles stream towards the tip. (AVI 294 kb)
Enlargement of the Spitzenkörper. (MPG 1195 kb)
- Genetic toolbox
Describing methods that can be used to investigate Candida albicans. As C. albicans is an obligate diploid, to generate null strains it is necessary to delete both copies of a gene, designated −/− in this Review. Strains with multiple auxotrophic markers have facilitated the generation of null strains. Other advances include using gene fusion to generate fluorescent and epitope-tagged proteins, and regulatable promoters.
- Germ tube
In this Review, a narrow, tube-like projection from a mother yeast cell that forms up to the end of the first cell cycle when an unbudded yeast cell is placed in hypha-inducing conditions.
A family of related proteins that form structures consisting of heteromeric filaments; first identified in Saccharomyces cerevisiae, in which they form a ring at the bud neck. Just before cytokinesis, the ring splits in two and this organizes the formation of the septum. The septin ring also acts as a diffusion barrier to the movement of proteins along the inner side of the plasma membrane.
(Vesicle-membrane soluble N-ethyl-maleimide-sensitive attachment protein receptors). Highly α-helical proteins that mediate the specific fusion of vesicles with target membranes. SNAREs have been classified into two complementary classes that are referred to as vesicle-membrane SNAREs (v-SNAREs) and target-membrane SNAREs (t-SNAREs).
The ability of hyphae to sense and grow along topographical cues in the environment such as cracks and ridges. This ability may help growth towards entry points in epithelia and endothelia.
The ability to sense and orientate along an electric field; Candidia albicans hyphae grow towards the cathode.
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