Negative regulation of filamentous growth in <i>Candida albicans</i> by Dig1p

Regan, Hannah; Scaduto, Christine M.; Hirakawa, Matthew P.; Gunsalus, Kearney T. W.; Correia-Mesquita, Tuana Oliveira; Sun, Yuan; Chen, Yaolin; Kumamoto, Carol A.; Bennett, Richard J.; Whiteway, Malcolm

doi:10.1111/mmi.13738

Cited by 10 publications

(10 citation statements)

References 59 publications

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“…Efg1 lies upstream of Hwp1 and its deletion eliminates the yeast-hyphal transition (Sharkey et al 1999). To test whether the filamentation exhibited by the mms21 null mutant is independent of Efg1, we deleted MMS21 in an efg1D/D strain as previously described (Regan et al 2017). As shown in Figure S1, the efg1D/D mutant cells were locked in the yeast form, but deleting both alleles of MMS21 (efg1D/D mms21D/D) resulted in filament formation as in the mms21 null cells.…”

Section: Filamentation In Mms21d/d Is Independent Of Efg1mentioning

confidence: 99%

Mms21: A Putative SUMO E3 Ligase in Candida albicans That Negatively Regulates Invasiveness and Filamentation, and Is Required for the Genotoxic and Cellular Stress Response

et al. 2018

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In the life cycle of the fungal pathogen Candida albicans, the formation of filamentous cells is a differentiation process that is critically involved in host tissue invasion, and in adaptation to host cell and environmental stresses. Here, we have used the Gene Replacement And Conditional Expression library to identify genes controlling invasiveness and filamentation; conditional repression of the library revealed 69 mutants that triggered these processes. Intriguingly, the genes encoding the small ubiquitin-like modifier (SUMO) E3 ligase Mms21, and all other tested members of the sumoylation pathway, were both nonessential and capable of triggering filamentation upon repression, suggesting an important role for sumoylation in controlling filamentation in C. albicans. We have investigated Mms21 in detail. Both Mms21 nulls (mms21D/D) and SP [Siz/Pias (protein inhibitor of activated signal transducer and activator of transcription)] domain (SUMO E3 ligase domain)-deleted mutants displayed invasiveness, filamentation, and abnormal nuclear segregation; filament formation occurred even in the absence of the hyphal transcription factor Efg1. Transcriptional analysis of mms21D/D showed an increase in expression from two-to eightfold above that of the wild-type for hyphal-specific genes, including ECE1, PGA13, PGA26, HWP1, ALS1, ALS3, SOD4, SOD5, UME6, and HGC1. The Mms21-deleted mutants were unable to recover from DNA-damaging agents like methyl methane sulfonate, hydroxyurea, hydrogen peroxide, and UV radiation, suggesting that the protein is important for genotoxic stress responses. In addition, the mms21D/D mutant displayed sensitivity to cell wall and thermal stresses, and to different antifungal drugs. All these findings suggest that Mms21 plays important roles in cellular differentiation, DNA damage and cellular stress responses, and in response to antifungal drugs.

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Section: Filamentation In Mms21d/d Is Independent Of Efg1mentioning

confidence: 99%

Mms21: A Putative SUMO E3 Ligase in Candida albicans That Negatively Regulates Invasiveness and Filamentation, and Is Required for the Genotoxic and Cellular Stress Response

et al. 2018

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“…The recruited Cst5-kinase complex engages with the membrane-associated Cst20 kinase, which phosphorylates and activates the MEKK Ste11, which in turn phosphorylates the MEK Hst7, which then acts on Cek1. The phosphorylated and activated Cek1 moves to the nucleus to ultimately trigger activation of Cph1, in part through the inactivation of Dig1 ( Regan et al 2017 ) resulting in the transcription of the mating-related genes. Our current observations suggest well as its enzymatic role, the MEKK Ste11 also plays a structural role in the mating process.…”

Section: Discussionmentioning

confidence: 99%

Signal-mediated localization of Candida albicans pheromone response pathway components

Costa

Omran

Law

et al. 2020

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Candida albicans opaque cells release pheromones to stimulate cells of opposite mating type to activate their pheromone response pathway. Although this fungal pathogen shares orthologous proteins involved in the process with Saccharomyces cerevisiae, the pathway in each organism has unique characteristics. We have used GFP-tagged fusion proteins to investigate the localization of the scaffold protein Cst5, as well as the MAP kinases Cek1 and Cek2, during pheromone response in C. albicans. In wild-type cells, pheromone treatment directed Cst5-GFP to surface puncta concentrated at the tips of mating projections. These puncta failed to form in cells defective in either the Gα or β subunits. However, they still formed in response to pheromone in cells missing Ste11, but with the puncta distributed around the cell periphery in the absence of mating projections. These puncta were absent from hst7Δ/Δ cells, but could be detected in the ste11Δ/Δ hst7Δ/Δ double mutant. Cek2-GFP showed a strong nuclear localization late in the response, consistent with a role in adaptation, while Cek1-GFP showed a weaker, but early increase in nuclear localization after pheromone treatment. Activation loop phosphorylation of both Cek1 and Cek2 required the presence of Ste11. In contrast to Cek2-GFP, which showed no localization signal in ste11Δ/Δ cells, Cek1-GFP showed enhanced nuclear localization that was pheromone independent in the ste11Δ/Δ mutant. The results are consistent with CaSte11 facilitating Hst7-mediated MAP kinase phosphorylation and also playing a potentially critical role in both MAP kinase and Cst5 scaffold localization.

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“…Ste12 is the probable point of integration of these two signals in O . polymorpha ( Fig 7 ), with the nitrogen-depletion signal (communicated through Efg1 and Rme1) increasing the level of STE12 transcription, and the pheromone-induced MAP kinase cascade activating Ste12 by releasing the ortholog of the inhibitor proteins Dig1/Dig2 [ 53 , 54 ]. We suggest that O .…”

Section: Discussionmentioning

confidence: 99%

“…cerevisiae , because C . albicans Efg1 also plays a role in mating and interacts with the Dig1/2 ortholog [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Flip/flop mating-type switching in the methylotrophic yeast Ogataea polymorpha is regulated by an Efg1-Rme1-Ste12 pathway

2017

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In haploid cells of Ogataea (Hansenula) polymorpha an environmental signal, nitrogen starvation, induces a reversible change in the structure of a chromosome. This process, mating-type switching, inverts a 19-kb DNA region to place either MATa or MATα genes under centromeric repression of transcription, depending on the orientation of the region. Here, we investigated the genetic pathway that controls switching. We characterized the transcriptomes of haploid and diploid O. polymorpha by RNAseq in rich and nitrogen-deficient media, and found that there are no constitutively a-specific or α-specific genes other than the MAT genes themselves. We mapped a switching defect in a sibling species (O. parapolymorpha strain DL-1) by interspecies bulk segregant analysis to a frameshift in the transcription factor EFG1, which in Candida albicans regulates filamentous growth and white-opaque switching. Gene knockout, overexpression and ChIPseq experiments show that EFG1 regulates RME1, which in turn regulates STE12, to achieve mating-type switching. All three genes are necessary both for switching and for mating. Overexpression of RME1 or STE12 is sufficient to induce switching without a nitrogen depletion signal. The homologous recombination genes RAD51 and RAD17 are also necessary for switching. The pathway controlling switching in O. polymorpha shares no components with the regulation of HO in S. cerevisiae, which does not involve any environmental signal, but it shares some components with mating-type switching in Kluyveromyces lactis and with white-opaque phenotypic switching in C. albicans.

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Negative regulation of filamentous growth in Candida albicans by Dig1p

Cited by 10 publications

References 59 publications

Mms21: A Putative SUMO E3 Ligase in Candida albicans That Negatively Regulates Invasiveness and Filamentation, and Is Required for the Genotoxic and Cellular Stress Response

Mms21: A Putative SUMO E3 Ligase in Candida albicans That Negatively Regulates Invasiveness and Filamentation, and Is Required for the Genotoxic and Cellular Stress Response

Signal-mediated localization of Candida albicans pheromone response pathway components

Flip/flop mating-type switching in the methylotrophic yeast Ogataea polymorpha is regulated by an Efg1-Rme1-Ste12 pathway

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