Candida albicans, the most commonly isolated human fungal pathogen, is responsible for a wide variety of systemic and mucosal infections. Immunocompromised individuals, including cancer patients on chemotherapy, AIDS patients, neonates, and organ transplant recipients, are particularly susceptible to infection. The ability of C. albicans to undergo a reversible morphological transition from single budding yeast cells 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. albicans morphological transition have been well-characterized, considerably less is known about the role of translational mechanisms. We have recently discovered that UME6, which encodes a key filament-specific transcriptional 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 filamentation under a variety of inducing conditions as well as the ability of UME6 expression to determine C. albicans morphology. The 5? UTR does not affect UME6 transcript levels or induction kinetics, but instead specifically reduces translational efficiency of UME6, as determined by a polysome profiling analysis. Importantly, the level of translational inhibition directed by the UME6 5? UTR is modulated by different filament-inducing conditions. A recent preliminary ribosome profiling experiment indicates the presence of two distinct ribosome stalling sites in the UME6 5? UTR, both of which are located immediately upstream of predicted complex stable RNA secondary structures. An RNA-seq analysis has demonstrated that in addition to UME6, a significant number of C. albicans genes involved in filamentation, and a variety of other virulence-related processes, including biofilm formation, adhesion, and secreted degradative enzyme production, also possess long 5? UTRs. Based on this evidence, our hypothesis is that 5? UTR-mediated translational efficiency mechanisms play an important role in controlling C. albicans morphology, virulence and virulence-related processes 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 expression by regulating UME6 translational efficiency via the 5? UTR, 2) determine the molecular mechanism(s) by which the UME6 5? UTR inhibits translational efficiency, 3) determine the broader role of 5? UTR-mediated translational efficiency mechanisms in controlling C. albicans virulence and a variety of virulence-related properties. These studies will provide a better understanding of how 5? UTR-mediated translational efficiency mechanisms control morphology and virulence in a major human fungal pathogen. Ultimately, common fungal-specific components of translational efficiency mechanisms that regulate fungal pathogenicity could serve as potential targets for the development of novel and more effective antifungal strategies.
Relevance to public health: Candida albicans, a major human fungal pathogen responsible for life- threatening yeast infections in a wide variety of immunocompromised individuals, possesses the ability to undergo a reversible morphological transition from yeast to filaments. This proposal seeks to determine how translational efficiency mechanisms control C. albicans morphology and virulence. Ultimately, this study will provide new information leading to the development of novel and more effective strategies to treat candidiasis.
