Roles of Candida albicans Sfl1 in Hyphal Development

Abstract

The ability to switch between different morphological forms is an important feature of Candida albicans and is relevant to its pathogenesis. Many conserved positive and negative transcription factors are involved in morphogenetic regulation of the two dimorphic fungi Candida albicans and Saccharomyces cerevisiae. In S. cerevisiae, the transcriptional repressor Sfl1 and the activator Flo8 function antagonistically in invasive and filamentous growth. We have previously reported that Candida albicans Flo8 is a transcription factor essential for hyphal development and virulence in C. albicans. To determine whether a similar negative factor exists in C. albicans, we identified Candida albicans Sfl1 as a functional homolog of the S. cerevisiae sfl1 mutant. Sfl1 is a negative regulator of hyphal development in C. albicans. Deletion of C. albicans SFL1 enhanced filamentous growth and hypha-specific gene expression in several media and at several growth temperatures. Overexpression of the SFL1 led to a significant reduction of filament formation. Both deletion and overexpression of the SFL1 attenuated virulence of C. albicans in a mouse model. Deleting FLO8 in an sfl1/sfl1 mutant completely blocked hyphal development in various growth conditions examined, suggesting that C. albicans Sfl1 may act as a negative regulator of filamentous growth by antagonizing Flo8 functions. We suggest that, similar to the case for S. cerevisiae, a combination of dual control by activation and repression of Flo8 and Sfl1 may contribute to the fine regulatory network in C. albicans morphogenesis responding to different environmental cues.

A comprehensive functional portrait of two heat shock factor-type transcriptional regulators involved in Candida albicans morphogenesis and virulence

“…Consistent with a transcriptional regulatory function, an Sfl1p-GFP fusion localized to the nucleus, while one hybrid lacZ reporter analyses in C. albicans correlated with a repressor function [37]. Importantly, either deletion or overexpression of SFL1 attenuated C. albicans virulence in a mouse model of systemic infection [38]. On the other hand, we and others have shown that deletion of SFL2 impaired filamentation in response to different cues, whereas SFL2 overexpression promoted hyphal growth, even under non hyphae-stimulating conditions [39][40][41].…”

“…Interestingly, the C. albicans genome encodes two structural homologs of ScSfl1p, namely Sfl1p and Sfl2p [37][38][39][40]. Either SFL1 or SFL2 functionally complement an S. cerevisiae sfl1 mutation [38,39] and encode important regulators of morphogenesis and virulence in C. albicans [37][38][39][40]. Intriguingly, although sharing structural homologies, Sfl1p and Sfl2p have antagonistic functions: while Sfl1p acts as a negative regulator of hyphal development, Sfl2p acts as a positive regulator of this process [37][38][39][40].…”

“…Intriguingly, although sharing structural homologies, Sfl1p and Sfl2p have antagonistic functions: while Sfl1p acts as a negative regulator of hyphal development, Sfl2p acts as a positive regulator of this process [37][38][39][40]. Functional analyses of C. albicans Sfl1p showed that deletion of SFL1 promoted filamentous growth and cell flocculation and correlated with induction of HSGs (ECE1, HWP1) and genes involved in cell adhesion (ALS1, ALS3), whereas its overexpression inhibited hyphal formation [37,38]. Consistent with a transcriptional regulatory function, an Sfl1p-GFP fusion localized to the nucleus, while one hybrid lacZ reporter analyses in C. albicans correlated with a repressor function [37].…”

“…ScSfl1p has dual activator/repressor functions, acting as a transcriptional repressor of flocculation-related genes and as an activator of stress-responsive genes [35,36]. Interestingly, the C. albicans genome encodes two structural homologs of ScSfl1p, namely Sfl1p and Sfl2p [37][38][39][40]. Either SFL1 or SFL2 functionally complement an S. cerevisiae sfl1 mutation [38,39] and encode important regulators of morphogenesis and virulence in C. albicans [37][38][39][40].…”

“…Either SFL1 or SFL2 functionally complement an S. cerevisiae sfl1 mutation [38,39] and encode important regulators of morphogenesis and virulence in C. albicans [37][38][39][40]. Intriguingly, although sharing structural homologies, Sfl1p and Sfl2p have antagonistic functions: while Sfl1p acts as a negative regulator of hyphal development, Sfl2p acts as a positive regulator of this process [37][38][39][40]. Functional analyses of C. albicans Sfl1p showed that deletion of SFL1 promoted filamentous growth and cell flocculation and correlated with induction of HSGs (ECE1, HWP1) and genes involved in cell adhesion (ALS1, ALS3), whereas its overexpression inhibited hyphal formation [37,38].…”