BRG1 and NRG1 form a novel feedback circuit regulating Candida albicans hypha formation and virulence

Abstract

Summary In the opportunistic fungal pathogen Candida albicans both cellular morphology and the capacity to cause disease are regulated by the transcriptional repressor Nrg1p. One of the genes repressed by Nrg1p is BRG1, which encodes a putative GATA family transcription factor. Deletion of both copies of this gene prevents hypha formation. We discovered that BRG1 over-expression is sufficient to overcome Nrg1p-mediated repression and drive the morphogenetic shift from yeast to hyphae even in the absence of environmental stimuli. We further observed that expression of BRG1 influences the stability of the NRG1 transcript, thus controlling filamentation through a feedback loop. Analysis of this phenomenon revealed that BRG1 expression is required for the induction of an antisense NRG1 transcript. This is the first demonstration of a role for mRNA stability in regulating the key C. albicans virulence trait: the ability to form hyphae.

Candida albicans hyphal initiation and elongation

“…Molecular mechanisms for the downregulation of NRG1 transcription are not known and likely complex. A recent publication suggests the involvement of an antisense NRG1 transcript in the downregulation of NRG1 transcript levels during hyphal development [57]. Further experiments are needed to elucidate how the cAMP-PKA pathway and its downstream transcriptional regulators control the downregulation of NRG1 transcription during hyphal initiation.…”

“…Brg1, a GATA family transcription factor, is required for both biofilm formation and hyphal elongation in C. albicans [57, 72–74]. Through a forward genetic screen, Brg1 was identified as the transcription factor that recruits Hda1 to promoters of hypha-specific genes for chromatin remodeling, leading to occlusion of Nrg1 binding during hyphal elongation [72].…”

Candida Biofilms: Development, Architecture, and Resistance

“…Proteomics analysis of biofilm matrix isolated using this optimized method revealed the presence of specific proteins (including glyceraldehyde 3-phosphate dehydrogenase and pyruvate kinase) in the biofilm matrix. Additional Candida genes implicated in biofilm formation include ACE2 ( 93 ), YWP1 ( 94 ), HWP1 ( 95 ), LL34 ( RIX7 ) ( 96 ), ALS3 ( 97 , 98 ), GAL10 ( 99 ), VPS1 ( 100 ), SUR7 ( 101 ), GUP1 ( 102 ), PEP12 ( 103 ), TPK1/2 ( 104 ), NRG1 (transcriptional repressor) and its target BRG1 (GATA family transcription factor) ( 105 ), UME6 (transcriptional regulator), HGC1 (a cyclin-related protein), SUN41 (a putative cell wall glycosidase), EFG1 ( 106 , 107 ), STV1 and VPH1 (Golgi/vacuolar subunits of vacuolar proton-translocating ATPase isoforms) ( 108 ), CEK1 (map kinase) ( 109 ), CDK8 ( 88 ), BCR1 ( 110 ), SPT20 ( 111 ), and SAC1 (PIP phosphatase) ( 112 ). In addition, quorum sensing molecules (such as 3R-hydroxy-tetradecaenoic acid [3R-HTDE, a beta-oxidation metabolite of endogenously present linoleic acid] [ 113 ]), farnesol ( 114 – 117 ), and cis -2-dodecenoic acid (BDSF) ( 118 ) and metabolic processes (e.g., carbohydrate assimilation, amino acid metabolism, and intracellular transport) ( 119 ) and glycolytic flux and hypoxia adaptation ( 120 ) have been suggested to play critical roles in Candida biofilm formation.…”

Candida albicans morphology: still in focus

“…A similar subtle level of regulation was shown when Hog1 basal activity was reduced [28]. A further link in the complex regulatory network was the identification of a novel feedback circuit formed by the known regulators Brg1 and Nrg1 form [29]. In addition, ceramide synthases [30] and regulation of actin organization [31] play important roles during filamentous growth.…”