Regulatory mechanisms controlling morphology and pathogenesis in Candida albicans

Abstract

Candida albicans, a major human fungal pathogen, can cause a wide variety of both mucosal and systemic infections, particularly in immunocompromised individuals. Multiple lines of evidence suggest a strong association between virulence and the ability of C. albicans to undergo a reversible morphological transition from yeast to filamentous cells in response to host environmental cues. Most previous studies on mechanisms important for controlling the C. albicans morphological transition have focused on signaling pathways and sequence-specific transcription factors. However, in recent years a variety of novel mechanisms have been reported, including those involving global transcriptional regulation and translational control. A large-scale functional genomics screen has also revealed new roles in filamentation for certain key biosynthesis pathways. This review article will highlight several of these exciting recent discoveries and discuss how they are relevant to the development of novel antifungal strategies. Ultimately, components of mechanisms that control C. albicans morphogenesis and pathogenicity could potentially serve as viable antifungal targets.

Figure 1.

Models for control of C. albicans morphology by global transcriptional mechanisms. (A) C. albicans shows a significant genomic expansion in members of the TLO gene family, which encodes fungal-specific subunits of the Mediator (Med) transcriptional complex, compared to the less pathogenic C. dubliniensis. Increased levels of Tlo proteins in C. albicans vs. C. dubliniensis results in a large “free” pool of Tlo protein, which competes with DNA-bound transcriptional activators (TA) for binding to co-activators (CA). As a consequence, certain genes encoding negative filamentous growth regulator genes (NFGs) may not be activated and cells grow as filaments. In C. dubliniensis there is no free pool of Tlo proteins, thus allowing transcriptional activators to make contact with the Mediator complex, which may result in activation of NFGs and promotion of growth in the yeast form. Alternative mechanisms involving indirect transcriptional regulation are also possible. GTFs = general transcription factors. Pol II = RNA polymerase II. (B) In a wild-type (WT) strain, upon exposure to appropriate filament-inducing conditions transcriptional activators (TA) promote assembly of a transcriptional pre-initiation complex, which increases the expression of hyphal-specific genes (HSGs) leading to hyphal growth. In the absence of Hir1, a key component of the replication-independent histone chaperone complex, histone (gray) density is increased, leading to a reduction in the amplitude of HSG expression and reduced filamentation. (C) Hsf1, a key C. albicans transcriptional regulator that responds to heat shock, promotes filamentation at high levels by increasing expression of positive filamentous growth regulators and reducing expression of negative regulators. Low levels of Hsf1 also promote filamentation through an Efg1-dependent pathway and by compromising function of the Hsp90 chaperone; filaments generated by Hsf1 depletion have distinct features and are multinucleate with reduced septa. Intermediate levels of Hsf1 result in yeast growth (adapted from Refs. 53,73).

Figure 2.

Regulation of C. albicans morphogenesis by 5’ UTR-mediated translational mechanisms. Translational efficiency of hyphal-specific genes (HSGs) could be altered by the formation of RNA secondary structures that block ribosome (blue) access. RNA-binding proteins (brown) that recognize these structures could also function to promote or inhibit ribosome accessibility. Alternatively, certain RNA-binding proteins (red) could block ribosome scanning along the 5’ UTR by steric hindrance. Translation may occur at short upstream uORF sequences in the 5’ UTR, thus preventing readthrough to the main ORF. Finally, a zip code sequence could specify alternative localization of HSGs to subcellular compartments that are not actively translated. Filament-inducing conditions may potentially impact translation of HSGs through one or several of the indicated mechanisms. Adapted in part from Refs. , .