Candida albicans glutathione reductase downregulates Efg1-mediated cyclic AMP/protein kinase A pathway and leads to defective hyphal growth and virulence upon decreased cellular methylglyoxal content accompanied by activating alcohol dehydrogenase and glycolytic enzymes

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 4; pp. 772 - 788
• Main Authors: Ku, MyungHee, Baek, Yong-Un, Kwak, Min-Kyu, Kang, Sa-Ouk
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2017
• Subjects: adenosine monophosphate; Alcohol dehydrogenase; Alcohol Dehydrogenase - metabolism; antifungal agents; Candida albicans; Candida albicans - growth & development; Candida albicans - metabolism; cell growth; cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA-Binding Proteins - metabolism; Down-Regulation - physiology; Efg1-mediated cyclic AMP/protein kinase A pathways; fructose-bisphosphate aldolase; Fungal Proteins - metabolism; Gene Expression Regulation, Fungal - physiology; gene overexpression; genes; Glutathione; Glutathione reductase; Glutathione Reductase - metabolism; glutathione-disulfide reductase; glyceraldehyde-3-phosphate dehydrogenase; glycolysis; Glycolysis - physiology; hyphae; Hyphae - growth & development; Hyphae - metabolism; Hyphae - physiology; Hyphal growth; Methylglyoxal; oxidants; protein kinases; Pyruvaldehyde - metabolism; signal transduction; Signal Transduction - physiology; thiols; transcription (genetics); Transcription Factors - metabolism; translation (genetics); virulence; Virulence - physiology; yeasts; Candida albicans; ORF; SPE; Alcohol dehydrogenase; EASC; ADH1; Glutathione reductase; mBBr; FOA; MG; Efg1-mediated cyclic AMP/protein kinase A pathways; GSH; HPLC; ODS; Glutathione; PBS; CAT1; GLR1; EAPX1; SOD; GR; FBA1; Methylglyoxal; ALO1; Hyphal growth; GCS1; TDH3
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2016.10.010

Glutathione reductase maintains the glutathione level in a reduced state. As previously demonstrated, glutathione is required for cell growth/division and its biosynthesizing-enzyme deficiency causes methylglyoxal accumulation. However, experimental evidences for reciprocal relationships between Cph1-/Efg1-mediated signaling pathway regulation and methylglyoxal production exerted by glutathione reductase on yeast morphology remain unclear. Glutathione reductase (GLR1) disruption/overexpression were performed to investigate aspects of pathological/morphological alterations in Candida albicans. These assumptions were proved by observations of cellular susceptibility to oxidants and thiols, and measurements of methylglyoxal and glutathione content in hyphal-inducing conditions mainly through the activity of GLR1-overexpressing cells. Additionally, the transcriptional/translational levels of bioenergetic enzymes and dimorphism-regulating protein kinases were examined in the strain. The GLR1-deficient strain was non-viable when GLR1 expression under the control of a CaMAL2 promoter was conditionally repressed, despite partial rescue of growth by exogenous thiols. During filamentation, non-growing hyphal GLR1-overexpressing cells exhibited resistance against oxidants and cellular methylglyoxal was significantly decreased, which concomitantly increased expressions of genes encoding energy-generating enzymes, including fructose-1,6-bisphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase, and alcohol dehydrogenase (ADH1), with remarkable repression of Efg1-signaling cascades. This is the first report that GLR1-triggered Efg1-mediated signal transduction repression strictly reduces dimorphic switching and virulence by maintaining the basal level of methylglyoxal following the enhanced gene expressions of glycolytic enzymes and ADH1. The Efg1 downregulatory mechanism by GLR1 expression has possibilities to involve in other complex network of signal pathways. Understanding how GLR1 overexpression affects multiple signaling pathways can help identify attractive targets for antifungal drugs. •Glutathione (GSH) is essentially required for Candida albicans cell growth.•Glutathione reductase (Glr1) regulates cellular methylglyoxal (MG) and reactive oxygen species (ROS).•The cellular MG and ROS contents were decreased in GLR1-overexpressing cells during filamentation.•Glr1 renders Efg1-mediated signaling pathway repression by enhancing glycolytic enzymes and ADH1.•The cellular MG acts as a signal molecule followed by Glr1, ADH1 and glycolytic enzyme expressions.