Toward an integrated model of capsule regulation in Cryptococcus neoformans.

Cryptococcus neoformans is an opportunistic fungal pathogen that causes serious human disease in immunocompromised populations. Its polysaccharide capsule is a key virulence factor which is regulated in response to growth conditions, becoming enlarged in the context of infection. We used microarray...

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Autores principales:	Brian C Haynes, Michael L Skowyra, Sarah J Spencer, Stacey R Gish, Matthew Williams, Elizabeth P Held, Michael R Brent, Tamara L Doering
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/4c885fe6149e499cbd2bb0e1b99cc7b8
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spelling	oai:doaj.org-article:4c885fe6149e499cbd2bb0e1b99cc7b82021-11-18T06:05:01ZToward an integrated model of capsule regulation in Cryptococcus neoformans.1553-73661553-737410.1371/journal.ppat.1002411https://doaj.org/article/4c885fe6149e499cbd2bb0e1b99cc7b82011-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22174677/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Cryptococcus neoformans is an opportunistic fungal pathogen that causes serious human disease in immunocompromised populations. Its polysaccharide capsule is a key virulence factor which is regulated in response to growth conditions, becoming enlarged in the context of infection. We used microarray analysis of cells stimulated to form capsule over a range of growth conditions to identify a transcriptional signature associated with capsule enlargement. The signature contains 880 genes, is enriched for genes encoding known capsule regulators, and includes many uncharacterized sequences. One uncharacterized sequence encodes a novel regulator of capsule and of fungal virulence. This factor is a homolog of the yeast protein Ada2, a member of the Spt-Ada-Gcn5 Acetyltransferase (SAGA) complex that regulates transcription of stress response genes via histone acetylation. Consistent with this homology, the C. neoformans null mutant exhibits reduced histone H3 lysine 9 acetylation. It is also defective in response to a variety of stress conditions, demonstrating phenotypes that overlap with, but are not identical to, those of other fungi with altered SAGA complexes. The mutant also exhibits significant defects in sexual development and virulence. To establish the role of Ada2 in the broader network of capsule regulation we performed RNA-Seq on strains lacking either Ada2 or one of two other capsule regulators: Cir1 and Nrg1. Analysis of the results suggested that Ada2 functions downstream of both Cir1 and Nrg1 via components of the high osmolarity glycerol (HOG) pathway. To identify direct targets of Ada2, we performed ChIP-Seq analysis of histone acetylation in the Ada2 null mutant. These studies supported the role of Ada2 in the direct regulation of capsule and mating responses and suggested that it may also play a direct role in regulating capsule-independent antiphagocytic virulence factors. These results validate our experimental approach to dissecting capsule regulation and provide multiple targets for future investigation.Brian C HaynesMichael L SkowyraSarah J SpencerStacey R GishMatthew WilliamsElizabeth P HeldMichael R BrentTamara L DoeringPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 12, p e1002411 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Brian C Haynes Michael L Skowyra Sarah J Spencer Stacey R Gish Matthew Williams Elizabeth P Held Michael R Brent Tamara L Doering Toward an integrated model of capsule regulation in Cryptococcus neoformans.
description	Cryptococcus neoformans is an opportunistic fungal pathogen that causes serious human disease in immunocompromised populations. Its polysaccharide capsule is a key virulence factor which is regulated in response to growth conditions, becoming enlarged in the context of infection. We used microarray analysis of cells stimulated to form capsule over a range of growth conditions to identify a transcriptional signature associated with capsule enlargement. The signature contains 880 genes, is enriched for genes encoding known capsule regulators, and includes many uncharacterized sequences. One uncharacterized sequence encodes a novel regulator of capsule and of fungal virulence. This factor is a homolog of the yeast protein Ada2, a member of the Spt-Ada-Gcn5 Acetyltransferase (SAGA) complex that regulates transcription of stress response genes via histone acetylation. Consistent with this homology, the C. neoformans null mutant exhibits reduced histone H3 lysine 9 acetylation. It is also defective in response to a variety of stress conditions, demonstrating phenotypes that overlap with, but are not identical to, those of other fungi with altered SAGA complexes. The mutant also exhibits significant defects in sexual development and virulence. To establish the role of Ada2 in the broader network of capsule regulation we performed RNA-Seq on strains lacking either Ada2 or one of two other capsule regulators: Cir1 and Nrg1. Analysis of the results suggested that Ada2 functions downstream of both Cir1 and Nrg1 via components of the high osmolarity glycerol (HOG) pathway. To identify direct targets of Ada2, we performed ChIP-Seq analysis of histone acetylation in the Ada2 null mutant. These studies supported the role of Ada2 in the direct regulation of capsule and mating responses and suggested that it may also play a direct role in regulating capsule-independent antiphagocytic virulence factors. These results validate our experimental approach to dissecting capsule regulation and provide multiple targets for future investigation.
format	article
author	Brian C Haynes Michael L Skowyra Sarah J Spencer Stacey R Gish Matthew Williams Elizabeth P Held Michael R Brent Tamara L Doering
author_facet	Brian C Haynes Michael L Skowyra Sarah J Spencer Stacey R Gish Matthew Williams Elizabeth P Held Michael R Brent Tamara L Doering
author_sort	Brian C Haynes
title	Toward an integrated model of capsule regulation in Cryptococcus neoformans.
title_short	Toward an integrated model of capsule regulation in Cryptococcus neoformans.
title_full	Toward an integrated model of capsule regulation in Cryptococcus neoformans.
title_fullStr	Toward an integrated model of capsule regulation in Cryptococcus neoformans.
title_full_unstemmed	Toward an integrated model of capsule regulation in Cryptococcus neoformans.
title_sort	toward an integrated model of capsule regulation in cryptococcus neoformans.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/4c885fe6149e499cbd2bb0e1b99cc7b8
work_keys_str_mv	AT brianchaynes towardanintegratedmodelofcapsuleregulationincryptococcusneoformans AT michaellskowyra towardanintegratedmodelofcapsuleregulationincryptococcusneoformans AT sarahjspencer towardanintegratedmodelofcapsuleregulationincryptococcusneoformans AT staceyrgish towardanintegratedmodelofcapsuleregulationincryptococcusneoformans AT matthewwilliams towardanintegratedmodelofcapsuleregulationincryptococcusneoformans AT elizabethpheld towardanintegratedmodelofcapsuleregulationincryptococcusneoformans AT michaelrbrent towardanintegratedmodelofcapsuleregulationincryptococcusneoformans AT tamaraldoering towardanintegratedmodelofcapsuleregulationincryptococcusneoformans
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Toward an integrated model of capsule regulation in Cryptococcus neoformans.

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