PgmNr Y3172: HSF-type transcription factors regulate morphogenesis in the human fungal pathogen Candida albicans.

Authors:
V. Basso; S. Znaidi; V. Lagage; C. d'Enfert; S. Bachellier-Bassi


Institutes
Institut Pasteur, Paris, FR.


Keyword: Networks

Abstract:

Candida albicans is a diploid fungus, commensal of most healthy individuals, but also one of the most prevalent human fungal pathogens. C. albicans has the ability to switch between a unicellular yeast form and filamentous forms (pseudohyphae or hyphae). This switch is important for virulence: yeast cells contribute to the colonization of mucosa and dissemination into the bloodstream, hyphal forms are important for crossing barriers, invasion of tissues and formation of biofilms. The transition is triggered by environmental cues (temperature, pH, CO2 …) and leads to the activation of hypha specific genes (HSGs). The transcriptional network behind the morphogenetic switch is very complex. Here, we report the role of the HSF-type transcription factors (TF) Sfl1, Sfl2 and Skn7. 

Sfl1 and Sfl2 antagonistically regulate the morphogenetic switch: Sfl1 has a negative role, whereas Sfl2 enhances filamentation in response to temperature. On the other hand, deletion of SKN7 is impairing hyphal growth on solid inducing media, while its overexpression (OE) triggers filamentation in the absence of hypha-inducing cues. We performed genome-wide ChIP analyses to uncover chromosomal regions bound by these TFs, and transcript profiling to identify genes regulated differentially upon their OE. Sfl1 and Sfl2, through divergent motifs, positively and negatively regulate a common set of targets, including repressors of hyphal growth (SSN6, NRG1, RFG1), activators of hyphal development (UME6, BRG1, TEC1) and yeast specific genes (RME1, RHD1, YWP1). Additionally, Sfl2 binds to and turns on the expression of many HSGs. We have shown that Sfl1 and Sfl2 interact with other regulators of morphogenesis (EFG1, UME6, TEC1, BRG1). Strikingly, Efg1 binds to targets of Sfl1 and Sfl2, and immunoprecipitates with either proteins. Furthermore, Skn7 binds to regions on the C. albicans genome, that also exhibit binding sites for other morphogenesis regulators, including Efg1, Ndt80, Sfl1 and Sfl2. Epistatic studies led us to a model where Skn7 modulate genes involved in hyphal growth, including several key factors of filamentation (DEF1, UME6, CPH1 and CZF1). Moreover, because Skn7 is also necessary for adaptation of C. albicans to oxidative stress, we measured intracellular Reactive Oxygen Species (ROS) levels upon induction of filamentous growth, and showed that Skn7 limits the increase of ROS associated with filamentation on solid media. In conclusion, we propose a regulatory network where C. albicans HSF-type regulators Sfl1, Sfl2 and Skn7 coordinate morphogenesis. This model fits in the wider and more complex morphogenetic transcriptional circuitry, implicating intimate functional interactions with other regulators.



Yeast Database Genetic Index
1. gene symbol: sfl1; systematic name: CR_05990C_A
2. gene symbol: sfl2; systematic name: C5_04830W_A
3. gene symbol: skn7; systematic name: C5_00240W_A