{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:48:55Z","timestamp":1792075735503,"version":"4.4.0"},"reference-count":53,"publisher":"American Society for Cell Biology (ASCB)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2005,5]]},"abstract":"<jats:p>The human pathogenic fungus Cryptococcus neoformans has diverged from a common ancestor into three biologically distinct varieties or sibling species over the past 10\u201340 million years. During evolution of these divergent forms, serotype A C. neoformans var. grubii has emerged as the most virulent and cosmopolitan pathogenic clade. Therefore, understanding how serotype A C. neoformans is distinguished from less successful pathogenic serotypes will provide insights into the evolution of fungal virulence. Here we report that the structurally conserved Pbs2-Hog1 MAP kinase cascade has been specifically recruited as a global regulator to control morphological differentiation and virulence factors in the highly virulent serotype A H99 clinical isolate, but not in the laboratory-generated and less virulent serotype D strain JEC21. The mechanisms of Hog1 regulation are strikingly different between the two strains, and the phosphorylation kinetics and localization pattern of Hog1 are opposite in H99 compared with JEC21 and other yeasts. The unique Hog1 regulatory pattern observed in the H99 clinical isolate is widespread in serotype A strains and is also present in some clinical serotype D isolates. Serotype A hog1\u0394 and pbs2\u0394 mutants are attenuated in virulence, further underscoring the role of the Pbs2-Hog1 MAPK cascade in the pathogenesis of cryptococcosis.<\/jats:p>","DOI":"10.1091\/mbc.e04-11-0987","type":"journal-article","created":{"date-parts":[[2005,2,24]],"date-time":"2005-02-24T01:29:24Z","timestamp":1109208564000},"page":"2285-2300","source":"Crossref","is-referenced-by-count":272,"title":["Specialization of the HOG Pathway and Its Impact on Differentiation and Virulence of<i>Cryptococcus neoformans<\/i>"],"prefix":"10.1091","volume":"16","author":[{"given":"Yong-Sun","family":"Bahn","sequence":"first","affiliation":[{"name":"Department of Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaihei","family":"Kojima","sequence":"additional","affiliation":[{"name":"Department of Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary M.","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Heitman","sequence":"additional","affiliation":[{"name":"Department of Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710"},{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710"},{"name":"Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710"},{"name":"Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1076","reference":[{"key":"REF1","doi-asserted-by":"crossref","unstructured":"Alepuz, P. M., Jovanovic, A., Reiser, V., and Ammerer, G. (2001). Stress-induced map kinase Hog1 is part of transcription activation complexes.Mol. Cell7, 767\u2013777.","DOI":"10.1016\/S1097-2765(01)00221-0"},{"key":"REF2","doi-asserted-by":"crossref","unstructured":"Alonso-Monge, R., Navarro-Garcia, F., Roman, E., Negredo, A. I., Eisman, B., Nombela, C., and Pla, J. (2003). The Hog1 mitogen-activated protein kinase is essential in the oxidative stress response and chlamydospore formation inCandida albicans.Eukaryot.Cell2, 351\u2013361.","DOI":"10.1128\/EC.2.2.351-361.2003"},{"key":"REF3","doi-asserted-by":"crossref","unstructured":"Alonso-Monge, R., Real, E., Wojda, I., Bebelman, J. P., Mager, W. H., and Siderius, M. (2001). Hyperosmotic stress response and regulation of cell wall integrity inSaccharomyces cerevisiaeshare common functional aspects.Mol. Microbiol.41, 717\u2013730.","DOI":"10.1046\/j.1365-2958.2001.02549.x"},{"key":"REF4","doi-asserted-by":"crossref","unstructured":"Alspaugh, J. A., Perfect, J. R., and Heitman, J. (1997).Cryptococcus neoformansmating and virulence are regulated by the G-protein alpha subunit GPA1 and cAMP.Genes Dev.11, 3206\u20133217.","DOI":"10.1101\/gad.11.23.3206"},{"key":"REF5","doi-asserted-by":"crossref","unstructured":"Alspaugh, J. A., Pukkila-Worley, R., Harashima, T., Cavallo, L. M., Funnell, D., Cox, G. M., Perfect, J. R., Kronstad, J. W., and Heitman, J. (2002). Adenylyl cyclase functions downstream of the G\u03b1 protein Gpa1 and controls mating and pathogenicity ofCryptococcus neoformans.Eukaryot. Cell1, 75\u201384.","DOI":"10.1128\/EC.1.1.75-84.2002"},{"key":"REF6","doi-asserted-by":"crossref","unstructured":"Bahn, Y. S., Hicks, J. K., Giles, S. S., Cox, G. M., and Heitman, J. (2004). Adenylyl cyclase-associated protein Aca1 regulates virulence and differentiation ofCryptococcus neoformansvia the cyclic AMP-protein kinase A cascade.Eukaryot. Cell3, 1476\u20131491.","DOI":"10.1128\/EC.3.6.1476-1491.2004"},{"key":"REF7","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.2.407"},{"key":"REF8","doi-asserted-by":"crossref","unstructured":"Casadevall, A., and Perfect, J. R. (1998).Cryptococcus neoformans.ASM Press, Washington, DC.","DOI":"10.1128\/9781555818241"},{"key":"REF9","doi-asserted-by":"crossref","unstructured":"Chang, Y. C., Wickes, B. L., Miller, G. F., Penoyer, L. A., and Kwon-Chung, K. J. (2000).Cryptococcus neoformansSTE12\u03b1 regulates virulence but is not essential for mating.J. Exp. Med.191, 871\u2013882.","DOI":"10.1084\/jem.191.5.871"},{"key":"REF10","doi-asserted-by":"crossref","unstructured":"Cox, G. M., Mukherjee, J., Cole, G. T., Casadevall, A., and Perfect, J. R. (2000). Urease as a virulence factor in experimental cryptococcosis.Infect. Immun.68, 443\u2013448.","DOI":"10.1128\/IAI.68.2.443-448.2000"},{"key":"REF11","doi-asserted-by":"crossref","unstructured":"Cruz, M. C., Sia, R. A., Olson, M., Cox, G. M., and Heitman, J. (2000). Comparison of the roles of calcineurin in physiology and virulence in sero-type D and serotype A strains ofCryptococcus neoformans.Infect. Immun.68, 982\u2013985.","DOI":"10.1128\/IAI.68.2.982-985.2000"},{"key":"REF12","doi-asserted-by":"crossref","unstructured":"D'Souza, C. A., Alspaugh, J. A., Yue, C., Harashima, T., Cox, G. M., Perfect, J. R., and Heitman, J. (2001). Cyclic AMP-dependent protein kinase controls virulence of the fungal pathogenCryptococcus neoformans.Mol. Cell. Biol.21, 3179\u20133191.","DOI":"10.1128\/MCB.21.9.3179-3191.2001"},{"key":"REF13","doi-asserted-by":"crossref","unstructured":"Davidson, R. C., Blankenship, J. R., Kraus, P. R., de Jesus Berrios, M., Hull, C. M., D'Souza, C., Wang, P., and Heitman, J. (2002). A PCR-based strategy to generate integrative targeting alleles with large regions of homology.Microbiology148, 2607\u20132615.","DOI":"10.1099\/00221287-148-8-2607"},{"key":"REF14","doi-asserted-by":"crossref","unstructured":"Davidson, R. C., Cruz, M. C., Sia, R. A., Allen, B., Alspaugh, J. A., and Heitman, J. (2000). Gene disruption by biolistic transformation in serotype D strains ofCryptococcus neoformans.Fungal Genet. Biol.29, 38\u201348.","DOI":"10.1006\/fgbi.1999.1180"},{"key":"REF15","doi-asserted-by":"crossref","unstructured":"Degols, G., Shiozaki, K., and Russell, P. (1996). Activation and regulation of the Spc1 stress-activated protein kinase inSchizosaccharomyces pombe.Mol. Cell. Biol.16, 2870\u20132877.","DOI":"10.1128\/MCB.16.6.2870"},{"key":"REF16","doi-asserted-by":"crossref","unstructured":"Fraser, J. A., Subaran, R. L., Nichols, C. B., and Heitman, J. (2003). Recapitulation of the sexual cycle of the primary fungal pathogenCryptococcus neoformansvar.gattii: implications for an outbreak on Vancouver Island, Canada.Eukaryot. Cell2, 1036\u20131045.","DOI":"10.1128\/EC.2.5.1036-1045.2003"},{"key":"REF17","doi-asserted-by":"crossref","unstructured":"Garcia-Rodriguez, L. J., Duran, A., and Roncero, C. (2000). Calcofluor anti-fungal action depends on chitin and a functional high-osmolarity glycerol response (HOG) pathway: evidence for a physiological role of theSaccharomyces cerevisiaeHOG pathway under noninducing conditions.J. Bacteriol.182, 2428\u20132437.","DOI":"10.1128\/JB.182.9.2428-2437.2000"},{"key":"REF18","doi-asserted-by":"crossref","unstructured":"Giaever, G.et al.(2002). Functional profiling of theSaccharomyces cerevisiaegenome.Nature418, 387\u2013391.","DOI":"10.1038\/nature00935"},{"key":"REF19","doi-asserted-by":"crossref","unstructured":"Granger, D. L., Perfect, J. R., and Durack, D. T. (1985). Virulence ofCryptococcus neoformans.Regulation of capsule synthesis by carbon dioxide.J. Clin. Invest.76, 508\u2013516.","DOI":"10.1172\/JCI112000"},{"key":"REF20","doi-asserted-by":"crossref","unstructured":"Hall, J. P., Cherkasova, V., Elion, E., Gustin, M. C., and Winter, E. (1996). The osmoregulatory pathway represses mating pathway activity inSaccharomyces cerevisiae: isolation of aFUS3mutant that is insensitive to the repression mechanism.Mol. Cell. Biol.16, 6715\u20136723.","DOI":"10.1128\/MCB.16.12.6715"},{"key":"REF21","doi-asserted-by":"crossref","unstructured":"Heitman, J., Allen, B., Alspaugh, J. A., and Kwon-Chung, K. J. (1999). On the origins of congenicMAT\u03b1 andMATastrains of the pathogenic yeastCryptococcus neoformans.Fungal Genet. Biol.28, 1\u20135.","DOI":"10.1006\/fgbi.1999.1155"},{"key":"REF22","doi-asserted-by":"crossref","unstructured":"Hicks, J. K., D'Souza, C. A., Cox, G. M., and Heitman, J. (2004). Cyclic AMP-dependent protein kinase catalytic subunits have divergent roles in virulence factor production in two varieties of the fungal pathogenCryptococcus neoformans.Eukaryot. Cell3, 14\u201326.","DOI":"10.1128\/EC.3.1.14-26.2004"},{"key":"REF23","doi-asserted-by":"crossref","unstructured":"Hoang, L. M., Maguire, J. A., Doyle, P., Fyfe, M., and Roscoe, D. L. (2004).Cryptococcus neoformansinfections at Vancouver Hospital and Health Sciences Centre (1997\u20132002): epidemiology, microbiology and histopathology.J. Med. Microbiol.53, 935\u2013940.","DOI":"10.1099\/jmm.0.05427-0"},{"key":"REF24","doi-asserted-by":"crossref","unstructured":"Hohmann, S. (2002). Osmotic stress signaling and osmoadaptation in yeasts.Microbiol. Mol. Biol. Rev.66, 300\u2013372.","DOI":"10.1128\/MMBR.66.2.300-372.2002"},{"key":"REF25","doi-asserted-by":"crossref","unstructured":"Hull, C. M., Davidson, R. C., and Heitman, J. (2002). Cell identity and sexual development inCryptococcus neoformansare controlled by the mating-type-specific homeodomain protein Sxi1alpha.Genes Dev.16, 3046\u20133060.","DOI":"10.1101\/gad.1041402"},{"key":"REF26","doi-asserted-by":"crossref","unstructured":"Hull, C. M., and Heitman, J. (2002). Genetics ofCryptococcus neoformans.Annu. Rev. Genet.36, 557\u2013615.","DOI":"10.1146\/annurev.genet.36.052402.152652"},{"key":"REF27","doi-asserted-by":"crossref","unstructured":"Jiang, B., Ram, A. F., Sheraton, J., Klis, F. M., and Bussey, H. (1995). Regulation of cell wall beta-glucan assembly:PTC1negatively affectsPBS2action in a pathway that includes modulation ofEXG1transcription.Mol. Gen. Genet.248, 260\u2013269.","DOI":"10.1007\/BF02191592"},{"key":"REF28","doi-asserted-by":"crossref","unstructured":"Kraus, P. R., Fox, D. S., Cox, G. M., and Heitman, J. (2003). TheCryptococcus neoformansMAP kinase Mpk1 regulates cell integrity in response to antifungal drugs and loss of calcineurin function.Mol. Microbiol.48, 1377\u20131387.","DOI":"10.1046\/j.1365-2958.2003.03508.x"},{"key":"REF29","doi-asserted-by":"crossref","unstructured":"Kwon-Chung, K. J., and Bennett, J. E. (1984). Epidemiologic differences between the two varieties ofCryptococcus neoformans.Am. J. Epidemiol.120, 123\u2013130.","DOI":"10.1093\/oxfordjournals.aje.a113861"},{"key":"REF30","doi-asserted-by":"crossref","unstructured":"Lengeler, K. B., Davidson, R. C., D'Souza, C., Harashima, T., Shen, W. C., Wang, P., Pan, X., Waugh, M., and Heitman, J. (2000). Signal transduction cascades regulating fungal development and virulence.Microbiol. Mol. Biol. Rev.64, 746\u2013785.","DOI":"10.1128\/MMBR.64.4.746-785.2000"},{"key":"REF31","doi-asserted-by":"crossref","unstructured":"Loftus, B. J.et al.(2005). The genome of the basidiomycetous yeast and human pathogenCryptococcus neoformans.Science307, 1321\u20131324.","DOI":"10.1126\/science.1103773"},{"key":"REF32","doi-asserted-by":"crossref","unstructured":"Maeda, T., Takekawa, M., and Saito, H. (1995). Activation of yeast PBS2 MAPKK by MAPKKKs or by binding of an SH3-containing osmosensor.Science269, 554\u2013558.","DOI":"10.1126\/science.7624781"},{"key":"REF33","doi-asserted-by":"crossref","unstructured":"Maeda, T., Wurgler-Murphy, S. M., and Saito, H. (1994). A two-component system that regulates an osmosensing MAP kinase cascade in yeast.Nature369, 242\u2013245.","DOI":"10.1038\/369242a0"},{"key":"REF34","doi-asserted-by":"crossref","unstructured":"Marra, R. E., Huang, J. C., Fung, E., Nielsen, K., Heitman, J., Vilgalys, R., and Mitchell, T. G. (2004). A genetic linkage map ofCryptococcus neoformansvarietyneoformansserotype D (Filobasidiella neoformans).Genetics167, 619\u2013631.","DOI":"10.1534\/genetics.103.023408"},{"key":"REF35","doi-asserted-by":"crossref","unstructured":"Mattison, C. P., Spencer, S. S., Kresge, K. A., Lee, J., and Ota, I. M. (1999). Differential regulation of the cell wall integrity mitogen-activated protein kinase pathway in budding yeast by the protein tyrosine phosphatases Ptp2 and Ptp3.Mol. Cell. Biol.19, 7651\u20137660.","DOI":"10.1128\/MCB.19.11.7651"},{"key":"REF36","doi-asserted-by":"crossref","unstructured":"Moore, T. D., and Edman, J. C. (1993). The alpha-mating type locus ofCryptococcus neoformanscontains a peptide pheromone gene.Mol. Cell. Biol.13, 1962\u20131970.","DOI":"10.1128\/MCB.13.3.1962"},{"key":"REF37","doi-asserted-by":"crossref","unstructured":"Nelson, R. T., Pryor, B. A., and Lodge, J. K. (2003). Sequence length required for homologous recombination inCryptococcus neoformans.Fungal Genet. Biol.38, 1\u20139.","DOI":"10.1016\/S1087-1845(02)00510-8"},{"key":"REF38","doi-asserted-by":"crossref","unstructured":"Nielsen, K., Cox, G. M., Wang, P., Toffaletti, D. L., Perfect, J. R., and Heitman, J. (2003). Sexual cycle ofCryptococcus neoformansvar.grubiiand virulence of congenic a and \u03b1 isolates.Infect. Immun.71, 4831\u20134841.","DOI":"10.1128\/IAI.71.9.4831-4841.2003"},{"key":"REF39","doi-asserted-by":"crossref","unstructured":"O'Rourke, S. M., and Herskowitz, I. (1998). The Hog1 MAPK prevents cross talk between the HOG and pheromone response MAPK pathways inSaccharomyces cerevisiae.Genes Dev.12, 2874\u20132886.","DOI":"10.1101\/gad.12.18.2874"},{"key":"REF40","doi-asserted-by":"crossref","unstructured":"O'Rourke, S. M., Herskowitz, I., and O'Shea, E. K. (2002). Yeast go the whole HOG for the hyperosmotic response.Trends Genet.18, 405\u2013412.","DOI":"10.1016\/S0168-9525(02)02723-3"},{"key":"REF41","doi-asserted-by":"crossref","unstructured":"Perfect, J. R., Ketabchi, N., Cox, G. M., Ingram, C. W., and Beiser, C. L. (1993). Karyotyping ofCryptococcus neoformansas an epidemiological tool.J. Clin. Microbiol.31, 3305\u20133309.","DOI":"10.1128\/JCM.31.12.3305-3309.1993"},{"key":"REF42","doi-asserted-by":"crossref","unstructured":"Posas, F., and Saito, H. (1997). Osmotic activation of the HOG MAPK pathway via Ste11p MAPKKK: scaffold role of Pbs2p MAPKK.Science276, 1702\u20131705.","DOI":"10.1126\/science.276.5319.1702"},{"key":"REF43","doi-asserted-by":"crossref","unstructured":"Posas, F., and Saito, H. (1998). Activation of the yeast SSK2 MAP kinase kinase kinase by the SSK1 two-component response regulator.EMBO J.17, 1385\u20131394.","DOI":"10.1093\/emboj\/17.5.1385"},{"key":"REF44","doi-asserted-by":"crossref","unstructured":"Posas, F., Witten, E. A., and Saito, H. (1998). Requirement of STE50 for osmostress-induced activation of the STE11 mitogen-activated protein kinase kinase kinase in the high-osmolarity glycerol response pathway.Mol. Cell. Biol.18, 5788\u20135796.","DOI":"10.1128\/MCB.18.10.5788"},{"key":"REF45","doi-asserted-by":"crossref","unstructured":"Posas, F., Wurgler-Murphy, S. M., Maeda, T., Witten, E. A., Thai, T. C., and Saito, H. (1996). Yeast HOG1 MAP kinase cascade is regulated by a multistep phosphorelay mechanism in the SLN1-YPD1-SSK1 \u201ctwo-component\u201d osmo-sensor.Cell86, 865\u2013875.","DOI":"10.1016\/S0092-8674(00)80162-2"},{"key":"REF46","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.10.4.1147"},{"key":"REF47","doi-asserted-by":"crossref","unstructured":"Speed, B., and Dunt, D. (1995). Clinical and host differences between infections with the two varieties ofCryptococcus neoformans.Clin. Infect. Dis.21, 28\u201334; discussion 35\u201336.","DOI":"10.1093\/clinids\/21.1.28"},{"key":"REF48","doi-asserted-by":"crossref","unstructured":"Van Wuytswinkel, O., Reiser, V., Siderius, M., Kelders, M. C., Ammerer, G., Ruis, H., and Mager, W. H. (2000). Response ofSaccharomyces cerevisiaeto severe osmotic stress: evidence for a novel activation mechanism of the HOG MAP kinase pathway.Mol. Microbiol,37, 382\u2013397.","DOI":"10.1046\/j.1365-2958.2000.02002.x"},{"key":"REF49","doi-asserted-by":"crossref","unstructured":"Wang, P., Cutler, J., King, J., and Palmer, D. (2004). Mutation of the regulator of G protein signaling Crg1 increases virulence inCryptococcus neoformans.Eukaryot. Cell3, 1028\u20131035.","DOI":"10.1128\/EC.3.4.1028-1035.2004"},{"key":"REF50","doi-asserted-by":"crossref","unstructured":"Wang, P., Nichols, C. B., Lengeler, K. B., Cardenas, M. E., Cox, G. M., Perfect, J. R., and Heitman, J. (2002). Mating-type-specific and nonspecific PAK kinases play shared and divergent roles inCryptococcus neoformans.Eukaryot. Cell1, 257\u2013272.","DOI":"10.1128\/EC.1.2.257-272.2002"},{"key":"REF51","doi-asserted-by":"crossref","unstructured":"Xu, J., Vilgalys, R., and Mitchell, T. G. (2000). Multiple gene genealogies reveal recent dispersion and hybridization in the human pathogenic fungusCryptococcus neoformans.Mol. Ecol.9, 1471\u20131481.","DOI":"10.1046\/j.1365-294x.2000.01021.x"},{"key":"REF52","doi-asserted-by":"crossref","unstructured":"Yue, C., Cavallo, L. M., Alspaugh, J. A., Wang, P., Cox, G. M., Perfect, J. R., and Heitman, J. (1999). The STE12\u03b1 homolog is required for haploid filamentation but largely dispensable for mating and virulence inCryptococcus neoformans.Genetics153, 1601\u20131615.","DOI":"10.1093\/genetics\/153.4.1601"},{"key":"REF53","doi-asserted-by":"crossref","unstructured":"Zaragoza, O., Fries, B. C., and Casadevall, A. (2003). Induction of capsule growth inCryptococcus neoformansby mammalian serum and CO2.Infect. Immun.71, 6155\u20136164.","DOI":"10.1128\/IAI.71.11.6155-6164.2003"}],"container-title":["Molecular Biology of the Cell"],"original-title":[],"language":"en","deposited":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T12:51:53Z","timestamp":1625489513000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.molbiolcell.org\/doi\/10.1091\/mbc.e04-11-0987"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,5]]},"references-count":53,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2005,5]]}},"alternative-id":["10.1091\/mbc.e04-11-0987"],"URL":"https:\/\/doi.org\/10.1091\/mbc.e04-11-0987","relation":{},"ISSN":["1059-1524","1939-4586"],"issn-type":[{"value":"1059-1524","type":"print"},{"value":"1939-4586","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,5]]}}}