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Role of an expanded inositol transporter repertoire in Cryptococcus neoformans sexual reproduction and virulence.

Xue C, Liu T, Chen L, Li W, Liu I, Kronstad JW, Seyfang A, Heitman J - MBio (2010)

Bottom Line: Expression of ITR genes in a Saccharomyces cerevisiae itr1 itr2 mutant lacking inositol transport can complement the slow-growth phenotype of this strain, confirming that ITR genes are bona fide inositol transporters.Deletion of the inositol 1-phosphate synthase gene INO1 in an itr1 or itr1a mutant background compromised virulence in a murine inhalation model, indicating the importance of inositol sensing and acquisition for fungal infectivity.Our study provides a platform for further understanding the roles of inositol in fungal physiology and virulence.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.

ABSTRACT
Cryptococcus neoformans and Cryptococcus gattii are globally distributed human fungal pathogens and the leading causes of fungal meningitis. Recent studies reveal that myo-inositol is an important factor for fungal sexual reproduction. That C. neoformans can utilize myo-inositol as a sole carbon source and the existence of abundant inositol in the human central nervous system suggest that inositol is important for Cryptococcus development and virulence. In accord with this central importance of inositol, an expanded myo-inositol transporter (ITR) gene family has been identified in Cryptococcus. This gene family contains two phylogenetically distinct groups, with a total of 10 or more members in C. neoformans and at least six members in the sibling species C. gattii. These inositol transporter genes are differentially expressed under inositol-inducing conditions based on quantitative real-time PCR analyses. Expression of ITR genes in a Saccharomyces cerevisiae itr1 itr2 mutant lacking inositol transport can complement the slow-growth phenotype of this strain, confirming that ITR genes are bona fide inositol transporters. Gene mutagenesis studies reveal that the Itr1 and Itr1A transporters are important for myo-inositol stimulation of mating and that functional redundancies among the myo-inositol transporters likely exist. Deletion of the inositol 1-phosphate synthase gene INO1 in an itr1 or itr1a mutant background compromised virulence in a murine inhalation model, indicating the importance of inositol sensing and acquisition for fungal infectivity. Our study provides a platform for further understanding the roles of inositol in fungal physiology and virulence.

No MeSH data available.


Related in: MedlinePlus

Phylogenetic analysis of myo-inositol transporter (Itr) proteins among different fungi. (A) myo-Inositol transporter homologs from the Hemiascomycota (S. cerevisiae, A. gossypii, and C. albicans), Euascomycota (N. crassa, Aspergillus  fumigatus, and C. immitis), Archiascomycota (S. pombe), Basidiomycota (U. maydis and C. neoformans var. grubii), and Zygomycota (R. oryzae) were identified based on BLAST searches. The human sodium-dependent inositol transporters served as outgroup controls. (B) Numbers of Itr homologs in different fungi.
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f3: Phylogenetic analysis of myo-inositol transporter (Itr) proteins among different fungi. (A) myo-Inositol transporter homologs from the Hemiascomycota (S. cerevisiae, A. gossypii, and C. albicans), Euascomycota (N. crassa, Aspergillus  fumigatus, and C. immitis), Archiascomycota (S. pombe), Basidiomycota (U. maydis and C. neoformans var. grubii), and Zygomycota (R. oryzae) were identified based on BLAST searches. The human sodium-dependent inositol transporters served as outgroup controls. (B) Numbers of Itr homologs in different fungi.

Mentions: When the group 1 and group 2 Itrs from Cryptococcus were compared with related Itr homologs from other fungi, group 1 was found to share a high level of identity with the Itrs in other yeasts, such as S. cerevisiae and S. pombe. There are two Itrs in S. cerevisiae and S. pombe, and both cluster within group 1. In most other ascomycetes with completed genome sequences, only one ITR gene was found in this group, including in hemiascomycetes (C. albicans and Ashbya gossypii) and euascomycetes (Coccidioides immitis and Neurospora crassa) (Fig. 3). Two basidiomycete genomes were used for comparison. The closely related species Tremella mesenterica has only one ITR homolog, while the corn smut fungus Ustilago maydis has two (Fig. 3). One exception in this group is the zygomycete Rhizopus oryzae, which has three Itr paralogs in group 1.


Role of an expanded inositol transporter repertoire in Cryptococcus neoformans sexual reproduction and virulence.

Xue C, Liu T, Chen L, Li W, Liu I, Kronstad JW, Seyfang A, Heitman J - MBio (2010)

Phylogenetic analysis of myo-inositol transporter (Itr) proteins among different fungi. (A) myo-Inositol transporter homologs from the Hemiascomycota (S. cerevisiae, A. gossypii, and C. albicans), Euascomycota (N. crassa, Aspergillus  fumigatus, and C. immitis), Archiascomycota (S. pombe), Basidiomycota (U. maydis and C. neoformans var. grubii), and Zygomycota (R. oryzae) were identified based on BLAST searches. The human sodium-dependent inositol transporters served as outgroup controls. (B) Numbers of Itr homologs in different fungi.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2912663&req=5

f3: Phylogenetic analysis of myo-inositol transporter (Itr) proteins among different fungi. (A) myo-Inositol transporter homologs from the Hemiascomycota (S. cerevisiae, A. gossypii, and C. albicans), Euascomycota (N. crassa, Aspergillus  fumigatus, and C. immitis), Archiascomycota (S. pombe), Basidiomycota (U. maydis and C. neoformans var. grubii), and Zygomycota (R. oryzae) were identified based on BLAST searches. The human sodium-dependent inositol transporters served as outgroup controls. (B) Numbers of Itr homologs in different fungi.
Mentions: When the group 1 and group 2 Itrs from Cryptococcus were compared with related Itr homologs from other fungi, group 1 was found to share a high level of identity with the Itrs in other yeasts, such as S. cerevisiae and S. pombe. There are two Itrs in S. cerevisiae and S. pombe, and both cluster within group 1. In most other ascomycetes with completed genome sequences, only one ITR gene was found in this group, including in hemiascomycetes (C. albicans and Ashbya gossypii) and euascomycetes (Coccidioides immitis and Neurospora crassa) (Fig. 3). Two basidiomycete genomes were used for comparison. The closely related species Tremella mesenterica has only one ITR homolog, while the corn smut fungus Ustilago maydis has two (Fig. 3). One exception in this group is the zygomycete Rhizopus oryzae, which has three Itr paralogs in group 1.

Bottom Line: Expression of ITR genes in a Saccharomyces cerevisiae itr1 itr2 mutant lacking inositol transport can complement the slow-growth phenotype of this strain, confirming that ITR genes are bona fide inositol transporters.Deletion of the inositol 1-phosphate synthase gene INO1 in an itr1 or itr1a mutant background compromised virulence in a murine inhalation model, indicating the importance of inositol sensing and acquisition for fungal infectivity.Our study provides a platform for further understanding the roles of inositol in fungal physiology and virulence.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.

ABSTRACT
Cryptococcus neoformans and Cryptococcus gattii are globally distributed human fungal pathogens and the leading causes of fungal meningitis. Recent studies reveal that myo-inositol is an important factor for fungal sexual reproduction. That C. neoformans can utilize myo-inositol as a sole carbon source and the existence of abundant inositol in the human central nervous system suggest that inositol is important for Cryptococcus development and virulence. In accord with this central importance of inositol, an expanded myo-inositol transporter (ITR) gene family has been identified in Cryptococcus. This gene family contains two phylogenetically distinct groups, with a total of 10 or more members in C. neoformans and at least six members in the sibling species C. gattii. These inositol transporter genes are differentially expressed under inositol-inducing conditions based on quantitative real-time PCR analyses. Expression of ITR genes in a Saccharomyces cerevisiae itr1 itr2 mutant lacking inositol transport can complement the slow-growth phenotype of this strain, confirming that ITR genes are bona fide inositol transporters. Gene mutagenesis studies reveal that the Itr1 and Itr1A transporters are important for myo-inositol stimulation of mating and that functional redundancies among the myo-inositol transporters likely exist. Deletion of the inositol 1-phosphate synthase gene INO1 in an itr1 or itr1a mutant background compromised virulence in a murine inhalation model, indicating the importance of inositol sensing and acquisition for fungal infectivity. Our study provides a platform for further understanding the roles of inositol in fungal physiology and virulence.

No MeSH data available.


Related in: MedlinePlus