{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:54:30Z","timestamp":1783349670472,"version":"3.54.6"},"reference-count":46,"publisher":"Rockefeller University Press","issue":"5","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2000,3,6]]},"abstract":"<jats:p>The Cryptococcus neoformans STE12\u03b1 gene, a homologue of Saccharomyces cerevisiae STE12, exists only in mating type (MAT)\u03b1 cells. In S. cerevisiae, STE12 was required for mating and filament formation. In C. neoformans, haploid fruiting on filament agar required STE12\u03b1. The ability to form hyphae, however, was not affected by deletion of STE12\u03b1 when convergently growing MATa strains were present. Furthermore, ste12\u03b1 disruptants were fertile when mated with MATa strains, albeit with reduced mating frequency. Most importantly, the virulence of a ste12\u03b1 disruptant of serotype D strain was significantly reduced in a mouse model. When the ste12\u03b1 locus was reconstituted with the wild-type allele by cotransformation, virulence was restored. Histopathological analysis demonstrated a reduction in capsular size of yeast cells, less severe cystic lesions, and stronger immune responses in meninges of mice infected with ste12\u03b1 cells than those of mice infected with STE12\u03b1 cells. Using reporter gene constructs, we found that STE12\u03b1 controls the expression of several phenotypes known to be involved in virulence, such as capsule and melanin production. These results demonstrate a clear molecular link between mating type and virulence in C. neoformans.<\/jats:p>","DOI":"10.1084\/jem.191.5.871","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:48:33Z","timestamp":1027702113000},"page":"871-882","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":130,"title":["<i>Cryptococcus neoformans STE12\u03b1<\/i> Regulates Virulence but Is Not Essential for Mating"],"prefix":"10.1084","volume":"191","author":[{"given":"Y.C.","family":"Chang","sequence":"first","affiliation":[{"name":"aLaboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Office of the Director, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.L.","family":"Wickes","sequence":"additional","affiliation":[{"name":"cDepartment of Microbiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.F.","family":"Miller","sequence":"additional","affiliation":[{"name":"bVeterinary Resources Program, Office of the Director, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.A.","family":"Penoyer","sequence":"additional","affiliation":[{"name":"aLaboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Office of the Director, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.J.","family":"Kwon-Chung","sequence":"additional","affiliation":[{"name":"aLaboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Office of the Director, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2000,3,6]]},"reference":[{"key":"2023072509100171300_R1","volume-title":"Medical Mycology","author":"Kwon-Chung","year":"1992"},{"key":"2023072509100171300_R2","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1128\/CMR.8.4.515","article-title":"Cryptococcosis in the era of AIDS\u2014100 years after the discovery of Cryptococcus neoformans","volume":"8","author":"Mitchell","year":"1995","journal-title":"Clin. Microbiol. Rev."},{"key":"2023072509100171300_R3","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1080\/00275514.1975.12019866","article-title":"A new genus, Filobasidiella, the perfect state of Cryptococcus neoformans","volume":"67","author":"Kwon-Chung","year":"1975","journal-title":"Mycologia."},{"key":"2023072509100171300_R4","first-page":"943","article-title":"A new species of Filobasidiella, the sexual state of Cryptococcus neoformans B and C serotypes","volume":"68","author":"Kwon-Chung","year":"1976","journal-title":"Mycologia."},{"key":"2023072509100171300_R5","doi-asserted-by":"crossref","first-page":"7327","DOI":"10.1073\/pnas.93.14.7327","article-title":"Dimorphism and haploid fruiting in Cryptococcus neoformansassociation with the alpha-mating type","volume":"93","author":"Wickes","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072509100171300_R6","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1046\/j.1365-2958.1997.6322001.x","article-title":"The Cryptococcus neoformans STE12alpha genea putative Saccharomyces cerevisiae STE12 homologue that is mating type specific","volume":"26","author":"Wickes","year":"1997","journal-title":"Mol. Microbiol."},{"key":"2023072509100171300_R7","first-page":"3765","article-title":"Functional domains of the yeast STE12 protein, a pheromone-responsive transcriptional activator","volume":"13","author":"Kirkman-Correia","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"2023072509100171300_R8","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/0092-8674(85)90288-0","article-title":"The yeast STE12 product is required for expression of two sets of cell-type specific genes","volume":"42","author":"Fields","year":"1985","journal-title":"Cell."},{"key":"2023072509100171300_R9","first-page":"3818","article-title":"Regulation by the yeast mating-type locus of STE12, a gene required for cell-type-specific expression","volume":"7","author":"Fields","year":"1987","journal-title":"Mol. Cell. Biol."},{"key":"2023072509100171300_R10","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1101\/gad.5.5.741","article-title":"Pheromone-dependent phosphorylation of the yeast STE12 protein correlates with transcriptional activation","volume":"5","author":"Song","year":"1991","journal-title":"Genes Dev."},{"key":"2023072509100171300_R11","doi-asserted-by":"crossref","first-page":"5703","DOI":"10.1073\/pnas.86.15.5703","article-title":"The yeast STE12 protein binds to the DNA sequence mediating pheromone induction","volume":"86","author":"Dolan","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072509100171300_R12","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/0092-8674(92)90079-R","article-title":"Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growthregulation by starvation and RAS","volume":"68","author":"Gimeno","year":"1992","journal-title":"Cell."},{"key":"2023072509100171300_R13","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.1101\/gad.8.24.2974","article-title":"Elements of a single MAP kinase cascade in Saccharomyces cerevisiae mediate two developmental programs in the same cell typemating and invasive growth","volume":"8","author":"Roberts","year":"1994","journal-title":"Genes Dev."},{"key":"2023072509100171300_R14","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/0092-8674(95)90402-6","article-title":"MAP kinase pathways in yeastfor mating and more","volume":"80","author":"Herskowitz","year":"1995","journal-title":"Cell."},{"key":"2023072509100171300_R15","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/S0962-8924(98)01298-7","article-title":"The control of filamentous differentiation and virulence in fungi","volume":"8","author":"Madhani","year":"1998","journal-title":"Trends Cell Biol."},{"key":"2023072509100171300_R16","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1093\/oxfordjournals.aje.a112628","article-title":"Distribution of \u03b1 and a mating types of Cryptococcus neoformans among natural and clinical isolates","volume":"108","author":"Kwon-Chung","year":"1978","journal-title":"Am. J. Epidemiol."},{"key":"2023072509100171300_R17","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1128\/iai.60.2.602-605.1992","article-title":"Genetic association of mating types and virulence in Cryptococcus neoformans","volume":"60","author":"Kwon-Chung","year":"1992","journal-title":"Infect. Immun."},{"key":"2023072509100171300_R18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1080\/02681219280000081","article-title":"Selection of ura5 and ura3 mutants from the two varieties of Cryptococcus neoformans on 5-fluoroorotic acid medium","volume":"30","author":"Kwon-Chung","year":"1992","journal-title":"J. Med. Vet. Mycol."},{"key":"2023072509100171300_R19","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1128\/jb.150.3.1212-1220.1982","article-title":"Biochemical studies of phenoloxidase and utilization of catecholamines in Cryptococcus neoformans","volume":"150","author":"Polacheck","year":"1982","journal-title":"J. Bacteriol."},{"key":"2023072509100171300_R20","first-page":"4912","article-title":"Complementation of a capsule-deficient mutation of Cryptococcus neoformans restores its virulence","volume":"14","author":"Chang","year":"1994","journal-title":"Mol. Cell. Biol."},{"key":"2023072509100171300_R21","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/BF00399484","article-title":"Taxonomic studies on Filobasidiella species and their anamorphs","volume":"48","author":"Kwon-Chung","year":"1982","journal-title":"Antonie Van Leeuwenhoek."},{"key":"2023072509100171300_R22","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1093\/infdis\/175.2.414","article-title":"Phospholipase activity in Cryptococcus neoformansa new virulence factor?","volume":"175","author":"Chen","year":"1997","journal-title":"J. Infect. Dis."},{"key":"2023072509100171300_R23","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1128\/IAI.66.5.2230-2236.1998","article-title":"Isolation of the third capsule-associated gene, CAP60, required for virulence in Cryptococcus neoformans","volume":"66","author":"Chang","year":"1998","journal-title":"Infect. Immun."},{"key":"2023072509100171300_R24","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1111\/j.1365-2958.1995.tb02335.x","article-title":"The Cryptococcus neoformans GAL7 gene and its use as an inducible promoter","volume":"16","author":"Wickes","year":"1995","journal-title":"Mol. Microbiol."},{"key":"2023072509100171300_R25","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s002940050366","article-title":"Construction of stable episomes in Cryptococcus neoformans","volume":"34","author":"Varma","year":"1998","journal-title":"Curr. Genet."},{"key":"2023072509100171300_R26","first-page":"4538","article-title":"Isolation of the URA5 gene from Cryptococcus neoformans var. neoformans and its use as a selective marker for transformation","volume":"10","author":"Edman","year":"1990","journal-title":"Mol. Cell. Biol."},{"key":"2023072509100171300_R27","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1128\/jb.175.5.1405-1411.1993","article-title":"Gene transfer in Cryptococcus neoformans by use of biolistic delivery of DNA","volume":"175","author":"Toffaletti","year":"1993","journal-title":"J. Bacteriol."},{"key":"2023072509100171300_R28","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0076-6879(91)94008-Z","article-title":"Assay of yeast mating reaction","volume":"194","author":"Sprague","year":"1991","journal-title":"Methods Enzymol."},{"key":"2023072509100171300_R29","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1128\/jb.176.3.656-664.1994","article-title":"Biochemical and molecular characterization of the diphenol oxidase of Cryptococcus neoformansidentification as a laccase","volume":"176","author":"Williamson","year":"1994","journal-title":"J. Bacteriol."},{"key":"2023072509100171300_R30","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1128\/iai.64.6.1977-1983.1996","article-title":"The second capsule gene of Cryptococcus neoformans, CAP64, is essential for virulence","volume":"64","author":"Chang","year":"1996","journal-title":"Infect. Immun."},{"key":"2023072509100171300_R31","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1172\/JCI112000","article-title":"Virulence of Cryptococcus neoformans. Regulation of capsule synthesis by carbon dioxide","volume":"76","author":"Granger","year":"1985","journal-title":"J. Clin. Invest."},{"key":"2023072509100171300_R32","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1126\/science.7992058","article-title":"Suppression of hyphal formation in Candida albicans by mutation of a STE12 homolog","volume":"266","author":"Liu","year":"1994","journal-title":"Science."},{"key":"2023072509100171300_R33","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1126\/science.8259520","article-title":"Elements of the yeast pheromone response pathway required for filamentous growth of diploids","volume":"262","author":"Liu","year":"1993","journal-title":"Science."},{"key":"2023072509100171300_R34","first-page":"2777","article-title":"Isolation of telomerelike sequences from Cryptococcus neoformans and their use in high-efficiency transformation","volume":"12","author":"Edman","year":"1992","journal-title":"Mol. Cell. Biol."},{"key":"2023072509100171300_R35","doi-asserted-by":"crossref","first-page":"S274","DOI":"10.1093\/cid\/10.Supplement_2.S274","article-title":"Molecular Koch's postulates applied to microbial pathogenicity","volume":"10","author":"Falkow","year":"1988","journal-title":"Rev. Infect. Dis."},{"key":"2023072509100171300_R36","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1099\/00221287-144-6-1691","article-title":"A novel quantitative mating assay for the fungal pathogen Cryptococcus neoformans provides insight into signalling pathways responding to nutrients and temperature","volume":"144","author":"Dong","year":"1998","journal-title":"Microbiology."},{"key":"2023072509100171300_R37","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1128\/jb.166.3.924-929.1986","article-title":"Genetic complementation in Cryptococcus neoformans","volume":"166","author":"Whelan","year":"1986","journal-title":"J. Bacteriol."},{"key":"2023072509100171300_R38","doi-asserted-by":"crossref","first-page":"22945","DOI":"10.1016\/S0021-9258(17)31601-0","article-title":"Identification of a putative transcription factor in Candida albicans that can complement the mating defect of Saccharomyces cerevisiae ste12 mutants","volume":"269","author":"Malathi","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2023072509100171300_R39","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1080\/00275514.1976.12019959","article-title":"Morphogenesis of Filobasidiella neoformans, the sexual state of Cryptococcus neoformans","volume":"68","author":"Kwon-Chung","year":"1976","journal-title":"Mycologia."},{"key":"2023072509100171300_R40","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1006\/emyc.1993.1033","article-title":"Microscopic observation of Ustilago maydis mating interaction","volume":"17","author":"Snetselaar","year":"1993","journal-title":"Exp. Mycol."},{"key":"2023072509100171300_R41","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1139\/b63-039","article-title":"Conjugation in Tremella mesenterica","volume":"41","author":"Bandoni","year":"1963","journal-title":"Can. J. Bot."},{"key":"2023072509100171300_R42","first-page":"1962","article-title":"The alpha-mating type locus of Cryptococcus neoformans contains a peptide pheromone gene","volume":"13","author":"Moore","year":"1993","journal-title":"Mol. Cell. Biol."},{"key":"2023072509100171300_R43"},{"key":"2023072509100171300_R44","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1093\/genetics\/153.4.1601","article-title":"The STE12alpha homolog is required for haploid filamentation but largely dispensable for mating and virulence in Cryptococcus neoformans","volume":"153","author":"Yue","year":"1999","journal-title":"Genetics."},{"key":"2023072509100171300_R45","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/BF00872392","article-title":"Phylogenetic relationships of Cryptococcus neoformans and some related basidiomycetous yeasts determined from partial large subunit rRNA sequences","volume":"63","author":"Gueho","year":"1993","journal-title":"Antonie Van Leeuwenhoek."},{"key":"2023072509100171300_R46","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1128\/JCM.37.3.838-840.1999","article-title":"Cryptococcus neoformans var. grubiiseparate varietal status for Cryptococcus neoformans serotype A isolates","volume":"37","author":"Franzot","year":"1999","journal-title":"J. Clin. Microbiol."}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/191\/5\/871\/1697620\/992058.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/191\/5\/871\/1697620\/992058.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T10:23:17Z","timestamp":1690280597000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/191\/5\/871\/20260\/Cryptococcus-neoformans-STE12-Regulates-Virulence"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,3,6]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2000,3,6]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.191.5.871","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,3,6]]}}}