TRANSLATIONAL CONTROL OF MORPHOLOGY AND VIRULENCE IN CANDIDA ALBICANS

Candida albicans, the most commonly isolated human fungal pathogen, is responsible for a wide variety ofsystemic and mucosal infections. Immunocompromised individuals, including cancer patients onchemotherapy, AIDS patients, neonates, and organ transplant recipients, are particularly susceptible toinfection. The ability of C. albicans to undergo a reversible morphological transition from single budding yeastcells to filaments (elongated cells attached end-to-end) is important for virulence as well as several virulence-related properties. While transcriptional and post-translational mechanisms that control the C. albicansmorphological transition have been well-characterized, considerably less is known about the role oftranslational mechanisms. We have recently discovered that UME6, which encodes a key filament-specifictranscriptional regulator of C. albicans morphology and virulence, possesses one of the longest 5?untranslated regions (UTRs) identified in fungi to date. The UME6 5? UTR inhibits C. albicans filamentationunder a variety of inducing conditions as well as the ability of UME6 expression to determine C. albicansmorphology. The 5? UTR does not affect UME6 transcript levels or induction kinetics, but instead specificallyreduces translational efficiency of UME6, as determined by a polysome profiling analysis. Importantly, thelevel of translational inhibition directed by the UME6 5? UTR is modulated by different filament-inducingconditions. A recent preliminary ribosome profiling experiment indicates the presence of two distinct ribosomestalling sites in the UME6 5? UTR, both of which are located immediately upstream of predicted complexstable RNA secondary structures. An RNA-seq analysis has demonstrated that in addition to UME6, asignificant number of C. albicans genes involved in filamentation, and a variety of other virulence-relatedprocesses, including biofilm formation, adhesion, and secreted degradative enzyme production, also possesslong 5? UTRs. Based on this evidence, our hypothesis is that 5? UTR-mediated translational efficiencymechanisms play an important role in controlling C. albicans morphology, virulence and virulence-relatedprocesses in response to host environmental cues. In order to address this hypothesis, we plan to: 1)determine how C. albicans filamentous growth signaling pathways control morphology and Ume6 expressionby regulating UME6 translational efficiency via the 5? UTR, 2) determine the molecular mechanism(s) bywhich the UME6 5? UTR inhibits translational efficiency, 3) determine the broader role of 5? UTR-mediatedtranslational efficiency mechanisms in controlling C. albicans virulence and a variety of virulence-relatedproperties. These studies will provide a better understanding of how 5? UTR-mediated translational efficiencymechanisms control morphology and virulence in a major human fungal pathogen. Ultimately, commonfungal-specific components of translational efficiency mechanisms that regulate fungal pathogenicity couldserve as potential targets for the development of novel and more effective antifungal strategies.