Abstract
Since its description in S. cerevisiae, the Regulation of Ace2 and Morphogenesis (RAM) pathway has been studied for nearly 20 years in multiple model and pathogenic fungi. In pathogenic fungi, the RAM pathway carries out many functions through mechanisms that remain to be defined in detail. Recently, we reported that Cbk1-mediated phosphorylation of the transcription factor Ace2 functions to repress the hyphae-to-yeast transition in Candida albicans. This transition is understudied relative to the yeast-to-hyphae transition. Subapical hyphal cell compartments are arrested in G1 until the point at which lateral yeast emerge. Here, we discuss this model and report new data indicating that a second G1 associated protein, the mitotic exit regulator Amn1. In S. cerevisiae diploid cells, Amn1 negatively regulates Ace2 at both the gene expression level through a negative feedback loop and at the protein level by targeting Ace2 for degradation. In C. albicans, Amn1 and Ace2 also form a feedback loop at the level of gene expression. Deletion of AMN1 decreases lateral yeast formation relative to wild type in maturing hyphae and is associated with decreased expression of PES1, a positive regulator of lateral yeast formation. These data indicate that the regulation of mitotic exit plays a role in determining the timing of lateral yeast emergence from hyphae in C. albicans. We also propose an integrated model for the interplay between the Cbk1-Ace2 axis and other hyphal stage regulators during the process of filamentation and transition back to yeast.
Highlights
Candida albicans is an important human fungal pathogen that causes both superficial, mucosal infections and deep organ, invasive disease in both immunocompetent and immunocompromised individuals (McCarty and Pappas 2016)
Because the ability to transition between these morphotypes affects the virulence of C. albicans, the processes that regulate these transitions have been the subject of intensive study for decades (Arkowitz and Bassilana 2020)
Increased interest in the hyphae to yeast transition has been driven in part by the relatively recent recognition that it plays an important role in biofilm pathobiology (Uppuluri et al 2010)
Summary
Candida albicans is an important human fungal pathogen that causes both superficial, mucosal infections and deep organ, invasive disease in both immunocompetent and immunocompromised individuals (McCarty and Pappas 2016). As the sub-apical compartments mature, the cytoplasm/vacuole ratio increases to the point where the cells exit from G1 and enter START (Barelle et al 2003), leading to the emergence of lateral yeast cells from subapical compartments. This cell biological model nicely fits the observed data, almost nothing is known about the molecular details underlying the mechanism of the hyphae-to-yeast transition. We discuss our recent work on the role of the Regulation of Ace and Morphogenesis (RAM) pathway in the regulation of hyphal-related processes (Wakade et al 2020) and present data providing new details regarding the role of the mitotic exit regulator Amn in the modulation of ACE2 expression and the formation of lateral yeast cells from hyphae
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