Sfp1 and Rtg3 reciprocally modulate carbon source‐conditional stress adaptation in the pathogenic yeast Candida albicans

Abstract

SummaryThe pathogenicity of the clinically important yeast, Candida albicans, is dependent on robust responses to host‐imposed stresses. These stress responses have generally been dissected in vitro at 30°C on artificial growth media that do not mimic host niches. Yet host inputs, such as changes in carbon source or temperature, are known to affect C. albicans stress adaptation. Therefore, we performed screens to identify novel regulators that promote stress resistance during growth on a physiologically relevant carboxylic acid and at elevated temperatures. These screens revealed that, under these ‘non‐standard’ growth conditions, numerous uncharacterised regulators are required for stress resistance in addition to the classical Hog1, Cap1 and Cta4 stress pathways. In particular, two transcription factors (Sfp1 and Rtg3) promote stress resistance in a reciprocal, carbon source‐conditional manner. SFP1 is induced in stressed glucose‐grown cells, whereas RTG3 is upregulated in stressed lactate‐grown cells. Rtg3 and Sfp1 regulate the expression of key stress genes such as CTA4, CAP1 and HOG1 in a carbon source‐dependent manner. These mechanisms underlie the stress sensitivity of C. albicans sfp1 cells during growth on glucose, and rtg3 cells on lactate. The data suggest that C. albicans exploits environmentally contingent regulatory mechanisms to retain stress resistance during host colonisation.

The yeast form of the fungus Candida albicans promotes persistence in the gut of gnotobiotic mice

“…921 and ORF19 . 4722 ) have been characterized elsewhere [ 30 – 33 ] but the fact that they also displayed a phenotype in our study validates the experimental model and screening approach. Another four deletion mutants ( zcf8 Δ/Δ [ orf19 .…”

The Regulatory Proteins Rtg1/3 Govern Sphingolipid Homeostasis in the Human-Associated Yeast Candida albicans

“…Yet, there seem to be direct links to the regulators as well. For instance, other studies have implicated Rtg1/3 in some facets of C. albicans sugar metabolism (Dalal et al, 2016;Kastora et al, 2017). Likewise, full-genome chromatin immunoprecipitation experiments have shown that Rtg1p and Rtg3p bind upstream of a large, eclectic set of metabolismrelated genes (Pé rez et al, 2013).…”

The Role of Secretory Pathways in Candida albicans Pathogenesis

“…In addition to the UPR, ER proteins are involved in maintaining a favorable environment for protein folding. A zinc finger transcription factor, Sfp1p, responds to carbon-conditional stress and oxidative stress in C. albicans [92,93]. Mutants lacking SFP1 were found to be more resistant to oxidative radicals and macrophage killing [91].…”

“…Mutants lacking SFP1 were found to be more resistant to oxidative radicals and macrophage killing [91]. Together with another transcription factor, Rtg3p, Sfp1p negatively regulates the transcription of stress response genes CAP1, CTA4, and HOG1 [89,[91][92][93][94]. Cap1p is a bZIP transcription factor that controls antioxidant gene expression and HOG1 encodes a transcription factor that activates a MAP-kinase cascade to result in resistance to oxidative stresses [91,92].…”

“…Together with another transcription factor, Rtg3p, Sfp1p negatively regulates the transcription of stress response genes CAP1, CTA4, and HOG1 [89,[91][92][93][94]. Cap1p is a bZIP transcription factor that controls antioxidant gene expression and HOG1 encodes a transcription factor that activates a MAP-kinase cascade to result in resistance to oxidative stresses [91,92]. Overaccumulation of reactive oxidative species (ROS) compromises cell wall integrity and affects the maturation of the proteins in the ER, impacting C. albicans virulence [95,96].…”