title: The Mannoprotein Cig1 supports iron acquisition from heme and virulence in the pathogenic fungus Cryptococcus neoformans.
abstract: Iron acquisition is critical for virulence of the human pathogenic fungus Cryptococcus neoformans. The cryptococcal transcript for the extracellular mannoprotein Cig1 is highly regulated by iron and abundant in iron-starved cells, suggesting a role in iron acquisition. Indeed, loss of Cig1 resulted in delayed growth on heme at physiological pH. Expression of CIG1 is regulated by the pH-responsive transcription factor Rim101, and loss of Rim101 also impaired growth on heme. A cig1Δ mutant was less susceptible than the wild-type strain to noniron metalloporphyrins, further indicating a role for Cig1 in heme uptake. Recombinant Cig1 exhibited the absorbance spectrum of a heme-binding protein upon heme titration, and Cig1 may therefore function as a hemophore at the cell surface. Cig1 contributed to virulence in a mouse model of cryptococcosis but only in a mutant that also lacked the high-affinity iron uptake system. Overall, Cig1-mediated heme uptake is a potential therapeutic target in C. neoformans.
authors: Michael Smith Laboratories and Department of Microbiology and Immunology, The University of British Columbia, Vancouver, BC, Canada.
authors: Brigitte
authors: B
authors: Cadieux
authors: Tianshun
authors: T
authors: Lian
authors: Guanggan
authors: G
authors: Hu
authors: Joyce
authors: J
authors: Wang
authors: Carmelo
authors: C
authors: Biondo
authors: Giuseppe
authors: G
authors: Teti
authors: Victor
authors: V
authors: Liu
authors: Michael E P
authors: ME
authors: Murphy
authors: A Louise
authors: AL
authors: Creagh
authors: James W
authors: JW
authors: Kronstad
mesh_terms: D000818:Animals; D015169:Colony Count, Microbial; D003453:Cryptococcosis / Q000382:microbiology / Q000473:pathology*; D003455:Cryptococcus neoformans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D006418:Heme / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013053:Spectrophotometry / Q000379:methods; D017186:Titrimetry; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D037521:Virulence Factors; D006418:Heme; D007501:Iron