Dataset Information

Sexual development in Cryptococcus neoformans requires CLP1, a target of the homeodomain transcription factors Sxi1alpha and Sxi2a.

ABSTRACT: Sexual development in the human fungal pathogen Cryptococcus neoformans is a multistep process that results in the formation of spores, the likely infectious particles. A critical step in this developmental process is the transition from bud-form growth to filamentous growth. This transition is controlled by the homeodomain transcription factors Sxi1alpha and Sxi2a, whose targets are largely unknown. Here we describe the discovery of a gene, CLP1, that is regulated by Sxi1alpha and Sxi2a and is essential for sexual development. In vitro binding studies also show that the CLP1 promoter is bound directly by Sxi1alpha and Sxi2a. The deletion of CLP1 leads to a block in sexual development after cell fusion but before filament formation, and cells without CLP1 are unable to grow vegetatively after cell fusion. Our findings lead to a model in which CLP1 is a downstream target of the Sxi proteins that functions to promote growth after mating and to establish the filamentous state, a critical step in the production of spores.

SUBMITTER: Ekena JL

PROVIDER: S-EPMC2224147 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Sexual development in Cryptococcus neoformans requires CLP1, a target of the homeodomain transcription factors Sxi1alpha and Sxi2a.

Ekena Joanne L JL Stanton Brynne C BC Schiebe-Owens Jessica A JA Hull Christina M CM

Eukaryotic cell 20071109 1

Sexual development in the human fungal pathogen Cryptococcus neoformans is a multistep process that results in the formation of spores, the likely infectious particles. A critical step in this developmental process is the transition from bud-form growth to filamentous growth. This transition is controlled by the homeodomain transcription factors Sxi1alpha and Sxi2a, whose targets are largely unknown. Here we describe the discovery of a gene, CLP1, that is regulated by Sxi1alpha and Sxi2a and is ...[more]

PMID: 17993575

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Project description:The eukaryotic serine/threonine protein phosphatase PP2A is a heterotrimeric enzyme composed of a scaffold A subunit, a regulatory B subunit, and a catalytic C subunit. Of the four known B subunits, the B"' subunit (known as striatin) interacts with the multi-protein striatin-interacting phosphatase and kinase (STRIPAK) complex. Orthologs of STRIPAK components were identified in C. neoformans, namely PP2AA/Tpd3, PP2AC/Pph22, PP2AB"'/Far8, STRIP/Far11, SLMAP/Far9, and Mob3. Structural modeling, protein domain analysis, and detected protein-protein interactions suggest C. neoformans STRIPAK is assembled similarly to the human and fungal orthologs. Here, STRIPAK components Pph22, Far8, and Mob3 were functionally characterized. Whole-genome sequencing revealed that mutations in STRIPAK complex subunits lead to increased segmental and chromosomal aneuploidy, suggesting STRIPAK functions in maintaining genome stability. We demonstrate that PPH22 is a haploinsufficient gene: heterozygous PPH22/pph22Δ mutant diploid strains exhibit defects in hyphal growth and sporulation and have a significant fitness disadvantage when grown in competition against a wild-type diploid. Deletion mutants pph22Δ, far8Δ, and mob3Δ exhibit defects in mating and sexual differentiation, including impaired hyphae, basidia, and basidiospore production. Loss of either PPH22 or FAR8 leads to growth defects at 30°C, severely reduced growth at elevated temperature, abnormal cell morphology, and impaired virulence. The pph22Δ and far8Δ mutants are also unable to grow in the presence of the calcineurin inhibitors cyclosporine A or FK506, and thus these mutations are synthetically lethal with loss of calcineurin activity. Conversely, mob3Δ mutants display increased thermotolerance, capsule production, and melanization, and are hypervirulent in a murine infection model. Taken together, these findings reveal that the C. neoformans STRIPAK complex plays an important role in genome stability, vegetative growth, sexual development, and virulence in this prominent human fungal pathogen.

Dataset Information

Sexual development in Cryptococcus neoformans requires CLP1, a target of the homeodomain transcription factors Sxi1alpha and Sxi2a.

Publications

Sexual development in Cryptococcus neoformans requires CLP1, a target of the homeodomain transcription factors Sxi1alpha and Sxi2a.

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