Control of Virulence Properties in the Major Human Oral Fungal Pathogen Candida albicans by the Asc1 Translational Regulator

ABSTRACT Normally found as a commensal in healthy individuals, Candida albicans is also a major human oral fungal pathogen in a wide variety of immunocompromised patients, including cancer and HIV/AIDS patients, which poses a severe risk as antifungal resistance emerges. C. albicans possesses several virulence properties, including the ability to undergo a reversible morphological transition from yeast to filaments and tolerate a variety of host environmental stresses. While transcriptional mechanisms controlling C. albicans virulence properties have been well-studied, considerably less is known about the role of translational mechanisms. Previous studies have shown that the Asc1 translational regulator controls C. albicans morphology and virulence. In the model yeast Saccharomyces cerevisiae Asc1 facilitates protein-protein interactions and functions in the SESA complex, also comprised of Smy1, Scp160, and Eap1, to direct gene-specific translational repression. Eap1 is an eIF4E- binding protein that regulates cap-dependent translation by disrupting the eIF4F complex. S. cerevisiae Asc1 also plays a role in regulating expression of many proteins involved in cellular morphology, osmotic stress, and translational regulation. Specifically, Asc1 post-transcriptionally regulates pseudohyphal development signaling components/transcription factors Ste12, Tec1, and Phd1 through their 5’ UTRs as well as Rap1 and Flo8. We have shown that C. albicans asc1 mutants are highly defective for filamentation and biofilm formation. These mutants are also highly resistant to cell wall stresses and rapamycin, but sensitive to oxidative and cell membrane stresses. Using double mutants, we have also shown genetic interactions between Asc1 and orf19.7034 (the C. albicans Eap1 ortholog) with respect to C. albicans stress responses, morphogenesis, and biofilm formation. Preliminary mass spectrometry data indicate that Asc1 interacts with C. albicans orthologs of SESA complex components, as well as other proteins involved in virulence properties, stress responses, and translation. We have also shown that C. albicans Asc1 is specifically important for controlling the protein levels of Ume6, a key transcriptional regulator of morphogenesis. Based on these findings, our hypothesis is that Asc1 mediates gene-specific translational regulation of C. albicans virulence properties and genetically interacts with SESA complex component orthologs to control C. albicans stress responses and filamentation. We will test this hypothesis by carrying out experiments that are focused on: 1) determining how interactions between Asc1 and other SESA complex component orthologs control C. albicans morphogenesis and host environmental stress responses and, 2) determining how Asc1 regulates the translation of C. albicans proteins specifically involved in cellular signaling pathways and virulence processes. While several antibiotics are known to target the bacterial translation machinery, translational mechanisms remain an unexplored and unexploited avenue for antifungal development. Thus, gaining a better understanding of the function of C. albicans Asc1 and the pathways it targets could lead to the development of novel and more effective antifungals for the treatment of oral candidiasis.