The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence.
Efficient carbon assimilation is critical for microbial growth and pathogenesis. The environmental yeast Saccharomyces cerevisiae is "Crabtree positive", displaying a rapid metabolic switch from the assimilation of alternative carbon sources to sugars. Following exposure to sugars, this sw...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-04-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1005566 |
| _version_ | 1818589541726945280 |
|---|---|
| author | Delma S Childers Ingrida Raziunaite Gabriela Mol Avelar Joanna Mackie Susan Budge David Stead Neil A R Gow Megan D Lenardon Elizabeth R Ballou Donna M MacCallum Alistair J P Brown |
| author_facet | Delma S Childers Ingrida Raziunaite Gabriela Mol Avelar Joanna Mackie Susan Budge David Stead Neil A R Gow Megan D Lenardon Elizabeth R Ballou Donna M MacCallum Alistair J P Brown |
| author_sort | Delma S Childers |
| collection | DOAJ |
| description | Efficient carbon assimilation is critical for microbial growth and pathogenesis. The environmental yeast Saccharomyces cerevisiae is "Crabtree positive", displaying a rapid metabolic switch from the assimilation of alternative carbon sources to sugars. Following exposure to sugars, this switch is mediated by the transcriptional repression of genes (carbon catabolite repression) and the turnover (catabolite inactivation) of enzymes involved in the assimilation of alternative carbon sources. The pathogenic yeast Candida albicans is Crabtree negative. It has retained carbon catabolite repression mechanisms, but has undergone posttranscriptional rewiring such that gluconeogenic and glyoxylate cycle enzymes are not subject to ubiquitin-mediated catabolite inactivation. Consequently, when glucose becomes available, C. albicans can continue to assimilate alternative carbon sources alongside the glucose. We show that this metabolic flexibility promotes host colonization and virulence. The glyoxylate cycle enzyme isocitrate lyase (CaIcl1) was rendered sensitive to ubiquitin-mediated catabolite inactivation in C. albicans by addition of a ubiquitination site. This mutation, which inhibits lactate assimilation in the presence of glucose, reduces the ability of C. albicans cells to withstand macrophage killing, colonize the gastrointestinal tract and cause systemic infections in mice. Interestingly, most S. cerevisiae clinical isolates we examined (67%) have acquired the ability to assimilate lactate in the presence of glucose (i.e. they have become Crabtree negative). These S. cerevisiae strains are more resistant to macrophage killing than Crabtree positive clinical isolates. Moreover, Crabtree negative S. cerevisiae mutants that lack Gid8, a key component of the Glucose-Induced Degradation complex, are more resistant to macrophage killing and display increased virulence in immunocompromised mice. Thus, while Crabtree positivity might impart a fitness advantage for yeasts in environmental niches, the more flexible carbon assimilation strategies offered by Crabtree negativity enhance the ability of yeasts to colonize and infect the mammalian host. |
| first_indexed | 2024-12-16T09:42:18Z |
| format | Article |
| id | doaj.art-480c42f57b65432d93a7ba882d68edff |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-16T09:42:18Z |
| publishDate | 2016-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-480c42f57b65432d93a7ba882d68edff2022-12-21T22:36:14ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742016-04-01124e100556610.1371/journal.ppat.1005566The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence.Delma S ChildersIngrida RaziunaiteGabriela Mol AvelarJoanna MackieSusan BudgeDavid SteadNeil A R GowMegan D LenardonElizabeth R BallouDonna M MacCallumAlistair J P BrownEfficient carbon assimilation is critical for microbial growth and pathogenesis. The environmental yeast Saccharomyces cerevisiae is "Crabtree positive", displaying a rapid metabolic switch from the assimilation of alternative carbon sources to sugars. Following exposure to sugars, this switch is mediated by the transcriptional repression of genes (carbon catabolite repression) and the turnover (catabolite inactivation) of enzymes involved in the assimilation of alternative carbon sources. The pathogenic yeast Candida albicans is Crabtree negative. It has retained carbon catabolite repression mechanisms, but has undergone posttranscriptional rewiring such that gluconeogenic and glyoxylate cycle enzymes are not subject to ubiquitin-mediated catabolite inactivation. Consequently, when glucose becomes available, C. albicans can continue to assimilate alternative carbon sources alongside the glucose. We show that this metabolic flexibility promotes host colonization and virulence. The glyoxylate cycle enzyme isocitrate lyase (CaIcl1) was rendered sensitive to ubiquitin-mediated catabolite inactivation in C. albicans by addition of a ubiquitination site. This mutation, which inhibits lactate assimilation in the presence of glucose, reduces the ability of C. albicans cells to withstand macrophage killing, colonize the gastrointestinal tract and cause systemic infections in mice. Interestingly, most S. cerevisiae clinical isolates we examined (67%) have acquired the ability to assimilate lactate in the presence of glucose (i.e. they have become Crabtree negative). These S. cerevisiae strains are more resistant to macrophage killing than Crabtree positive clinical isolates. Moreover, Crabtree negative S. cerevisiae mutants that lack Gid8, a key component of the Glucose-Induced Degradation complex, are more resistant to macrophage killing and display increased virulence in immunocompromised mice. Thus, while Crabtree positivity might impart a fitness advantage for yeasts in environmental niches, the more flexible carbon assimilation strategies offered by Crabtree negativity enhance the ability of yeasts to colonize and infect the mammalian host.https://doi.org/10.1371/journal.ppat.1005566 |
| spellingShingle | Delma S Childers Ingrida Raziunaite Gabriela Mol Avelar Joanna Mackie Susan Budge David Stead Neil A R Gow Megan D Lenardon Elizabeth R Ballou Donna M MacCallum Alistair J P Brown The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence. PLoS Pathogens |
| title | The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence. |
| title_full | The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence. |
| title_fullStr | The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence. |
| title_full_unstemmed | The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence. |
| title_short | The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence. |
| title_sort | rewiring of ubiquitination targets in a pathogenic yeast promotes metabolic flexibility host colonization and virulence |
| url | https://doi.org/10.1371/journal.ppat.1005566 |
| work_keys_str_mv | AT delmaschilders therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT ingridaraziunaite therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT gabrielamolavelar therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT joannamackie therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT susanbudge therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT davidstead therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT neilargow therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT megandlenardon therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT elizabethrballou therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT donnammaccallum therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT alistairjpbrown therewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT delmaschilders rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT ingridaraziunaite rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT gabrielamolavelar rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT joannamackie rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT susanbudge rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT davidstead rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT neilargow rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT megandlenardon rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT elizabethrballou rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT donnammaccallum rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence AT alistairjpbrown rewiringofubiquitinationtargetsinapathogenicyeastpromotesmetabolicflexibilityhostcolonizationandvirulence |