title: Factors supporting cysteine tolerance and sulfite production in Candida albicans.
abstract: The amino acid cysteine has long been known to be toxic at elevated levels for bacteria, fungi, and humans. However, mechanisms of cysteine tolerance in microbes remain largely obscure. Here we show that the human pathogenic yeast Candida albicans excretes sulfite when confronted with increasing cysteine concentrations. Mutant construction and phenotypic analysis revealed that sulfite formation from cysteine in C. albicans relies on cysteine dioxygenase Cdg1, an enzyme with similar functions in humans. Environmental cysteine induced not only the expression of the CDG1 gene in C. albicans, but also the expression of SSU1, encoding a putative sulfite efflux pump. Accordingly, the deletion of SSU1 resulted in enhanced sensitivity of the fungal cells to both cysteine and sulfite. To study the regulation of sulfite/cysteine tolerance in more detail, we screened a C. albicans library of transcription factor mutants in the presence of sulfite. This approach and subsequent independent mutant analysis identified the zinc cluster transcription factor Zcf2 to govern sulfite/cysteine tolerance, as well as cysteine-inducible SSU1 and CDG1 gene expression. cdg1Δ and ssu1Δ mutants displayed reduced hypha formation in the presence of cysteine, indicating a possible role of the newly proposed mechanisms of cysteine tolerance and sulfite secretion in the pathogenicity of C. albicans. Moreover, cdg1Δ mutants induced delayed mortality in a mouse model of disseminated infection. Since sulfite is toxic and a potent reducing agent, its production by C. albicans suggests diverse roles during host adaptation and pathogenicity.
authors: Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Junior Research Group Fundamental Molecular Biology of Pathogenic Fungi, Jena, Germany.
authors: Florian
authors: F
authors: Hennicke
authors: Maria
authors: M
authors: Grumbt
authors: Ulrich
authors: U
authors: Lermann
authors: Nico
authors: N
authors: Ueberschaar
authors: Katja
authors: K
authors: Palige
authors: Bettina
authors: B
authors: Böttcher
authors: Ilse D
authors: ID
authors: Jacobsen
authors: Claudia
authors: C
authors: Staib
authors: Joachim
authors: J
authors: Morschhäuser
authors: Michel
authors: M
authors: Monod
authors: Bernhard
authors: B
authors: Hube
authors: Christian
authors: C
authors: Hertweck
authors: Peter
authors: P
authors: Staib
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency / Q000235:genetics*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002177:Candidiasis / Q000382:microbiology / Q000401:mortality; D003545:Cysteine / Q000378:metabolism* / Q000494:pharmacology; D050558:Cysteine Dioxygenase / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D025301:Hyphae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D013447:Sulfites / Q000378:metabolism* / Q000494:pharmacology; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D027321:Anion Transport Proteins; D005656:Fungal Proteins; D013447:Sulfites; D014157:Transcription Factors; D050558:Cysteine Dioxygenase; D015032:Zinc; D003545:Cysteine