Regulation of Candida albicans Hyphal Morphogenesis by Endogenous Signals

Abstract

Candida albicans is a human commensal fungus that is able to assume several morphologies, including yeast, hyphal, and pseudohyphal. Under a range of conditions, C. albicans performs a regulated switch to the filamentous morphology, characterized by the emergence of a germ tube from the yeast cell, followed by a mold-like growth of branching hyphae. This transition from yeast to hyphal growth has attracted particular attention, as it has been linked to the virulence of C. albicans as an opportunistic human pathogen. Signal transduction pathways that mediate the induction of the hyphal transcription program upon the imposition of external stimuli have been extensively investigated. However, the hyphal morphogenesis transcription program can also be induced by internal cellular signals, such as inhibition of cell cycle progression, and conversely, the inhibition of hyphal extension can repress hyphal-specific gene expression, suggesting that endogenous cellular signals are able to modulate hyphal gene expression as well. Here we review recent developments in the regulation of the hyphal morphogenesis of C. albicans, with emphasis on endogenous morphogenetic signals.

Using genetically encoded heme sensors to probe the mechanisms of heme uptake and homeostasis inCandida albicans

“…One striking observation is that, in addition to iron starvation conditions, the CFEM hemophores involved in heme uptake are also among the most strongly induced genes under hyphal induction conditions (Azadmanesh et al, 2017;Roy and Kornitzer, 2019). C. albicans is a dimorphic pathogen, capable of switching from a yeast to a hyphal (mold) morphology under a variety of conditions such as elevated temperature, the presence of serum, the bacterial and fungal cell wall precursor N-acetyl glucosamine, among others (Sudbery et al, 2004;Basso et al, 2019;Kornitzer, 2019). While there is no evidence that the CFEM hemophores are required for hyphal morphogenesis, it is possible that hyphal-inducing conditions signify a heme-rich environment, be it the gut lumen or the mucosal surface, which would promote heme uptake even when iron is relatively abundant.…”

N-Acetylglucosamine Regulates Morphogenesis and Virulence Pathways in Fungi

“…A broad range of factors stimulate C. albicans to switch to hyphal growth. In addition to GlcNAc these include serum, nutritional factors such as certain amino acids or low nitrogen medium, and environmental conditions including high CO 2 , alkaline pH, contact with a solid matrix, and an ambient temperature of 37 • C [2,4,[6][7][8]. GlcNAc is one of the strongest inducers of hyphal growth, which has made it a useful tool for exploring the mechanisms underlying this morphological transition ( Figure 2).…”

“…The switch to hyphal growth is also significant in that it usually coincides with the induction of virulence factors, such as adhesins, that are important for biofilm formation, superoxide dismutase to counteract oxidative stress in the host, and secreted proteases that liberate nutrients and degrade components of the host immune response [3][4][5]. A diverse set of conditions induce hyphal growth including elevated temperature (37 • C), neutral or alkaline pH of the ambient medium, CO 2 , serum, interaction with a solid extracellular matrix, and certain nutrients including GlcNAc and amino acids [2,4,[6][7][8]. However, GlcNAc stands out as being one of the strongest inducers of hyphal growth.…”

The zinc cluster transcription factor Rha1 is a positive filamentation regulator in Candida albicans

“…Transcriptional control of cellular processes is critical for normal functioning of the medically important opportunistic fungal pathogen, Candida albicans, Central to this regulation are the DNA-binding transcription factors (TFs) that generally associate with target sequences in the promoters of regulated genes. The bound factors serve to activate or repress transcription in response to signals that typically represent either internal cellular states or external conditions (1,2). One of the main classes of C. albicans transcription factors are the zinc cluster proteins, named because of a cysteine-rich region that coordinates a zinc atom as part of the DNA binding domain of the protein (3).…”