Heme oxygenase in Candida albicans is regulated by hemoglobin and is necessary for metabolism of exogenous heme and hemoglobin to alpha-biliverdin.
Candida albicans is an opportunistic pathogen that has adapted uniquely to life in mammalian hosts. One of the host factors recognized by this yeast is hemoglobin, which binds to a specific cell surface receptor. In addition to its regulating the expression of adhesion receptors on the yeast, we have found that hemoglobin induces the expression of a C. albicans heme oxygenase (CaHmx1p). Hemoglobin transcriptionally induces the CaHMX1 gene independent of the presence of inorganic iron in the medium. A Renilla luciferase reporter driven by the CaHMX1 promoter demonstrated rapid activation of transcription by hemoglobin and (cobalt protoporphyrin IX) globin but not by apoglobin or other proteins. In contrast, iron deficiency or exogenous hemin did not activate the reporter until after 3 h, suggesting that induction of the promoter by hemoglobin is mediated by receptor signaling rather than heme or iron flux into the cell. As observed following disruption of the Saccharomyces cerevisiae ortholog, HMX1, a CaHMX1 null mutant was unable to grow under iron restriction. This suggests a role for CaHmx1p in inorganic iron acquisition. CaHMX1 encodes a functional heme oxygenase. Exogenous heme or hemoglobin is exclusively metabolized to alpha-biliverdin. CaHMX1 is required for utilization of these exogenous substrates, indicating that C. albicans heme oxygenase confers a nutritional advantage for growth in mammalian hosts.
Pendrak
Michael L
ML
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1500, USA.
Chao
Mark P
MP
Yan
S Steve
SS
Roberts
David D
DD
D000595:Amino Acid Sequence; D000818:Animals; D001664:Biliverdine / Q000737:chemistry; D002176:Candida albicans / Q000201:enzymology*; D002851:Chromatography, High Pressure Liquid; D003035:Cobalt / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006418:Heme / Q000737:chemistry; D006419:Heme Oxygenase (Decyclizing) / Q000737:chemistry* / Q000378:metabolism; D006427:Hemin / Q000737:chemistry; D006454:Hemoglobins / Q000737:chemistry*; D006801:Humans; D006868:Hydrolysis; D007501:Iron / Q000737:chemistry; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014346:Trypanosoma brucei brucei / Q000472:pathogenicity*; D014774:Virulence
D018076:DNA, Complementary; D006454:Hemoglobins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D003035:Cobalt; D006418:Heme; D012313:RNA; D006427:Hemin; D007501:Iron; D008156:Luciferases; D006419:Heme Oxygenase (Decyclizing); D001664:Biliverdine