title: Regulation of copper toxicity by Candida albicans GPA2.
abstract: Copper is an essential nutrient that is toxic to cells when present in excess. The fungal pathogen Candida albicans employs several mechanisms to survive in the presence of excess copper, but the molecular pathways that govern these responses are not completely understood. We report that deletion of GPA2, which specifies a G-protein α subunit, confers increased resistance to excess copper and propose that the increased resistance is due to a combination of decreased copper uptake and an increase in copper chelation by metallothioneins. This is supported by our observations that a gpa2Δ/Δ mutant has reduced expression of the copper uptake genes, CTR1 and FRE7, and a marked decrease in copper accumulation following exposure to high copper levels. Furthermore, deletion of GPA2 results in an increased expression of the copper metallothionein gene, CRD2. Gpa2p functions upstream in the cyclic AMP (cAMP)-protein kinase A (PKA) pathway to govern hyphal morphogenesis. The copper resistance phenotype of the gpa2Δ/Δ mutant can be reversed by artificially increasing the intracellular concentration of cAMP. These results provide evidence for a novel role of the PKA pathway in regulation of copper homeostasis. Furthermore, the connection between the PKA pathway and copper homeostasis appears to be conserved in the pathogen Cryptococcus neoformans but not in the nonpathogenic Saccharomyces cerevisiae.
authors.affiliation: Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Schwartz
authors.forename: Karen T
authors.initials: KT
authors.lastname: Olarte
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Michalek
authors.forename: Gurjinder S
authors.initials: GS
authors.lastname: Jandu
authors.forename: Sarah L J
authors.initials: SL
authors.lastname: Michel
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Bruno
mesh_terms: D002104:Cadmium / Q000633:toxicity; D002176:Candida albicans / Q000166:cytology / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D002945:Cisplatin / Q000494:pharmacology; D003300:Copper / Q000633:toxicity*; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D005800:Genes, Fungal / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D007501:Iron / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012834:Silver / Q000633:toxicity
chemical_list: D005656:Fungal Proteins; D044385:GTP-Binding Protein alpha Subunits; D002104:Cadmium; D012834:Silver; D003300:Copper; D000242:Cyclic AMP; D007501:Iron; D017868:Cyclic AMP-Dependent Protein Kinases; D002945:Cisplatin