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

Abstract

Sfl1p and Sfl2p are two homologous heat shock factor-type transcriptional regulators that antagonistically control morphogenesis in Candida albicans, while being required for full pathogenesis and virulence. To understand how Sfl1p and Sfl2p exert their function, we combined genome-wide location and expression analyses to reveal their transcriptional targets in vivo together with the associated changes of the C. albicans transcriptome. We show that Sfl1p and Sfl2p bind to the promoter of at least 113 common targets through divergent binding motifs and modulate directly the expression of key transcriptional regulators of C. albicans morphogenesis and/or virulence. Surprisingly, we found that Sfl2p additionally binds to the promoter of 75 specific targets, including a high proportion of hyphal-specific genes (HSGs; HWP1, HYR1, ECE1, others), revealing a direct link between Sfl2p and hyphal development. Data mining pointed to a regulatory network in which Sfl1p and Sfl2p act as both transcriptional activators and repressors. Sfl1p directly represses the expression of positive regulators of hyphal growth (BRG1, UME6, TEC1, SFL2), while upregulating both yeast form-associated genes (RME1, RHD1, YWP1) and repressors of morphogenesis (SSN6, NRG1). On the other hand, Sfl2p directly upregulates HSGs and activators of hyphal growth (UME6, TEC1), while downregulating yeast form-associated genes and repressors of morphogenesis (NRG1, RFG1, SFL1). Using genetic interaction analyses, we provide further evidences that Sfl1p and Sfl2p antagonistically control C. albicans morphogenesis through direct modulation of the expression of important regulators of hyphal growth. Bioinformatic analyses suggest that binding of Sfl1p and Sfl2p to their targets occurs with the co-binding of Efg1p and/or Ndt80p. We show, indeed, that Sfl1p and Sfl2p targets are bound by Efg1p and that both Sfl1p and Sfl2p associate in vivo with Efg1p. Taken together, our data suggest that Sfl1p and Sfl2p act as central ''switch on/off'' proteins to coordinate the regulation of C. albicans morphogenesis.

The expression of the Candida albicans gene SAP4 during hyphal formation in human serum and in adhesion to monolayer cell culture of colorectal carcinoma Caco-2 (ATCC)

“…In fact, we found that filamentous cells were produced by the efg1/efg1 mutant but the double cph1/cph1 efg1/efg1 mutant was extremely defective for filamentation. Consistent with this view is report of Znaidi et al [37] that Efg1 is not required for filamentation during tissue invasion. Based on previous data [2,38] we selected colorectal carcinoma (Caco-2) to quantify C. albicans cells and to characteristic of morphologies produced in contact with cells surface during adherence assay as well as to demonstrate whether the expression of SAP4 gene as well as EFG1 or CPH1 are responsible for adhesion.…”

“…Lo et al [5] and Znaidi et al [37] showed that strains lacking Efg1 or/ and Cph1 are defective in efficient hyphae formation and the cph1/cph1 efg1/efg1 double mutant is unable to fully undergo morphogenesis even under hyphae inducing conditions. Our previous data acquired in laboratory culture conditions [10] indicated that the cph1/cph1 strain forms true hyphae normally (even though very rarely) in comparison to efg1/efg1 as well as cph1/cph1 efg1/efg1 fully defective in true hyphae formation under human serum influence.…”

The Candida Pathogenic Species Complex

“…Specific repression of SFL2 in C. albicans was identified by Spiering et al (2010). SFL2 is a major regulator of morphogenesis in C. albicans and acts together with a homolog SFL1 to regulate expression of hyphal-and yeast-specific genes (Znaidi et al 2013).…”

When green and red mycology meet: Impressions from an interdisciplinary forum on virulence mechanisms of phyto- and human-pathogenic fungi

“…39,40 Christophe D'Enfert from the Institute Pasteur in Paris, France, gave an update on regulatory networks of C. albicans morphogenesis, focusing on heat shock responsive transcription factors that play apparently antagonistic regulatory roles in hyphae formation despite binding to overlapping regions of target gene promoters; among these, a gene product essential for chlamydospore formation could be identified. 41 Furthermore, the function of a heat shock factor type DNA binding protein as master regulator for transcriptional regulators of morphology was highlighted. Finally in this session, Stephanie Diezmann from Bath, UK, shared her findings about the Hsp90 heat shock protein of C. albicans and how it affects fungal genome ploidy as well as stress responses.…”

“…Di Pietro (S) 31,32 Fungal spore components determine the interaction with immune cells A. Brakhage (S) 38 Regulatory networks of C. albicans morphogenesis are complex C. D'Enfert (S) 41 Experimental evolution reveals unexpected factors of fungal virulence S. Brunke (Y) 75,76 Candida albicans produces a toxic surprise: Candidalysin J. Naglik (S) 56 Coprinopsis cinerea produces potent fungal defense effectors M. K€ unzler (S) [59][60][61] The fungal cell wall acts as immunological & drug target N. Gow (S) 70 Copper detoxification supports A. fumigatus virulence N. Osherov (Po) 77 Note. a P: plenary lecture, S: session talk, Y: young researcher presentation, Po: poster plant pathogenic fungi and might reveal natural products that are active in either host, be it plant or human.…”