scholarly journals A natural histone H2A variant lacking the Bub1 phosphorylation site and regulated depletion of centromeric histone CENP-A foster evolvability in Candida albicans

PLoS Biology ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. e3000331 ◽  
Author(s):  
Cedric A. Brimacombe ◽  
Jordan E. Burke ◽  
Jahan-Yar Parsa ◽  
Sandra Catania ◽  
Teresa R. O’Meara ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Phosphorylation Site ◽  
Histone H2a

scholarly journals Chromatin rewiring mediates programmed evolvability via aneuploidy

2018 ◽  
Author(s):  
Cedric A. Brimacombe ◽  
Jordan E. Burke ◽  
Jahan-Yar Parsa ◽  
Jessica N. Witchley ◽  
Laura S. Burrack ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Phosphorylation Site ◽  
Rapid Evolution ◽  
Histone H3 ◽  
Antifungal Drugs ◽  
High Fidelity ◽  
Histone H2a ◽  
Human Pathogen ◽  
Chromosome Missegregation ◽  
Mitosis And Meiosis

Eukaryotes have evolved elaborate mechanisms to ensure that chromosomes segregate with high fidelity during mitosis and meiosis1, and yet specific aneuploidies can be adaptive during environmental stress2,3. Here, we identify a chromatin-based system for inducible aneuploidy in a human pathogen. Candida albicans utilizes chromosome missegregation to acquire resistance to antifungal drugs4,5 and for ploidy reduction after mating6. We discovered that the ancestor of C. albicans and two related pathogens evolved a variant of histone H2A that lacks the conserved phosphorylation site for Bub1 kinase7, a key regulator of chromosome segregation1. Expression of this variant controls the rates of aneuploidy and antibiotic resistance in this species. Moreover, CENP-A/Cse4, the histone H3 that specifies centromeres, is depleted from tetraploid mating products and virtually eliminated from cells exposed to aneuploidy-promoting cues. Thus, changes in chromatin regulation can confer the capacity for rapid evolution in eukaryotes.

scholarly journals Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal Pathogen Candida albicans

2021 ◽  
Vol 11 ◽  
Author(s):  
Leenah Alaalm ◽  
Julia L. Crunden ◽  
Mark Butcher ◽  
Ulrike Obst ◽  
Ryann Whealy ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Environmental Stress ◽  
Stress Responses ◽  
Fungal Pathogens ◽  
Phosphorylation Site ◽  
Pathogenic Fungi ◽  
Phenotypic Characterization ◽  
Fungal Virulence ◽  
Post Translational Modifications ◽  
Virulence Traits

The highly conserved, ubiquitous molecular chaperone Hsp90 is a key regulator of cellular proteostasis and environmental stress responses. In human pathogenic fungi, which kill more than 1.6 million patients each year worldwide, Hsp90 governs cellular morphogenesis, drug resistance, and virulence. Yet, our understanding of the regulatory mechanisms governing fungal Hsp90 function remains sparse. Post-translational modifications are powerful components of nature’s toolbox to regulate protein abundance and function. Phosphorylation in particular is critical in many cellular signaling pathways and errant phosphorylation can have dire consequences for the cell. In the case of Hsp90, phosphorylation affects its stability and governs its interactions with co-chaperones and clients. Thereby modulating the cell’s ability to cope with environmental stress. Candida albicans, one of the leading human fungal pathogens, causes ~750,000 life-threatening invasive infections worldwide with unacceptably high mortality rates. Yet, it remains unknown if and how Hsp90 phosphorylation affects C. albicans virulence traits. Here, we show that phosphorylation of Hsp90 is critical for expression of virulence traits. We combined proteomics, molecular evolution analyses and structural modeling with molecular biology to characterize the role of Hsp90 phosphorylation in this non-model pathogen. We demonstrated that phosphorylation negatively affects key virulence traits, such as the thermal stress response, morphogenesis, and drug susceptibility. Our results provide the first record of a specific Hsp90 phosphorylation site acting as modulator of fungal virulence. Post-translational modifications of Hsp90 could prove valuable in future exploitations as antifungal drug targets.

scholarly journals Hyphal Chain Formation in Candida albicans: Cdc28-Hgc1 Phosphorylation of Efg1 Represses Cell Separation Genes

2009 ◽  
Vol 29 (16) ◽  
pp. 4406-4416 ◽  
Author(s):  
Allen Wang ◽  
Prashna Pala Raniga ◽  
Shelley Lane ◽  
Yang Lu ◽  
Haoping Liu
Keyword(s):  
Candida Albicans ◽  
Cell Separation ◽  
Target Gene ◽  
Target Genes ◽  
Phosphorylation Site ◽  
Hyphal Growth ◽  
Gene Promoters ◽  
Cyclin Dependent Kinase ◽  
Yeast Growth ◽  
Chain Formation

ABSTRACT Cell chain formation is a characteristic of filamentous growth in fungi. How it is regulated developmentally in multimorphic fungi is not known. In Candida albicans, degradation of septa during yeast growth is accomplished by enzymes encoded by Ace2 activated genes expressed in G1. We found that phosphorylation of a conserved developmental regulator, Efg1, by the cyclin-dependent kinase Cdc28-Hgc1 (hypha-specific G1 cyclin) downregulates Ace2 target genes during hyphal growth in G1. A strain containing a threonine-to-alanine mutation at a conserved Cdc28 phosphorylation site of Efg1 displays a loss of hypha-specific repression of these genes and impaired cell chain formation, mimicking the hgc1 deletion, whereas a strain containing the threonine to aspartic acid mutation leads to a downregulation of these genes and cell chain formation during yeast growth. Furthermore, the phosphomimic mutation can suppress cell separation defects of hgc1. Efg1 also displays preferential association with Ace2 target gene promoters during hyphal growth. We show that convergent regulation of Ace2 and Efg1 defines the transcriptional program of cell chain formation.

scholarly journals BRCT Domain Interactions with Phospho-Histone H2A Target Crb2 to Chromatin at Double-Strand Breaks and Maintain the DNA Damage Checkpoint

2010 ◽  
Vol 30 (19) ◽  
pp. 4732-4743 ◽  
Author(s):  
Sevil Sofueva ◽  
Li-Lin Du ◽  
Oliver Limbo ◽  
Jessica S. Williams ◽  
Paul Russell
Keyword(s):  
Dna Damage ◽  
Phosphorylation Site ◽  
Binding Pocket ◽  
Double Strand Breaks ◽  
Histone H2a ◽  
Histone H4 ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Domain Interactions ◽  
And Function

ABSTRACT Relocalization of checkpoint proteins to chromatin flanking DNA double-strand breaks (DSBs) is critical for cellular responses to DNA damage. Schizosaccharomyces pombe Crb2, which mediates Chk1 activation by Rad3ATR, forms ionizing radiation-induced nuclear foci (IRIF). Crb2 C-terminal BRCT domains (BRCT2) bind histone H2A phosphorylated at a C-terminal SQ motif by Tel1ATM and Rad3ATR, although the functional significance of this interaction is controversial. Here, we show that polar interactions of Crb2 serine-548 and lysine-619 with the phosphate group of phospho-H2A (γ-H2A) are critical for Crb2 IRIF formation and checkpoint function. Mutations of these BRCT2 domain residues have additive effects when combined in a single allele. Combining either mutation with an allele that eliminates the threonine-215 cyclin-dependent kinase phosphorylation site completely abrogates Crb2 IRIF and function. We propose that cooperative phosphate interactions in the BRCT2 γ-H2A-binding pocket of Crb2, coupled with tudor domain interactions with lysine-20 dimethylation of histone H4, facilitate stable recruitment of Crb2 to chromatin surrounding DSBs, which in turn mediates efficient phosphorylation of Chk1 that is required for a sustained checkpoint response. This mechanism of cooperative interactions with the γ-H2A/X phosphate is likely conserved in S. pombe Brc1 and human Mdc1 genome maintenance proteins.

scholarly journals Cooperative Control of Crb2 by ATM Family and Cdc2 Kinases Is Essential for the DNA Damage Checkpoint in Fission Yeast

2005 ◽  
Vol 25 (24) ◽  
pp. 10721-10730 ◽  
Author(s):  
Toru M. Nakamura ◽  
Bettina A. Moser ◽  
Li-Lin Du ◽  
Paul Russell
Keyword(s):  
Dna Damage ◽  
Fission Yeast ◽  
Cooperative Control ◽  
Genetic Interaction ◽  
Phosphorylation Site ◽  
Dna Damage Checkpoint ◽  
Histone H2a ◽  
Histone H4 ◽  
Checkpoint Response ◽  
Kinase Phosphorylation

ABSTRACT The cellular responses to double-stranded breaks (DSBs) typically involve the extensive accumulation of checkpoint proteins in chromatin surrounding the damaged DNA. One well-characterized example involves the checkpoint protein Crb2 in the fission yeast Schizosaccharomyces pombe. The accumulation of Crb2 at DSBs requires the C-terminal phosphorylation of histone H2A (known as γ-H2A) by ATM family kinases in chromatin surrounding the break. It also requires the constitutive methylation of histone H4 on lysine-20 (K20). Interestingly, neither type of histone modification is essential for the Crb2-dependent checkpoint response. However, H4-K20 methylation is essential in a crb2-T215A strain that lacks a cyclin-dependent kinase phosphorylation site in Crb2. Here we explain this genetic interaction by describing a previously overlooked effect of the crb2-T215A mutation. We show that crb2-T215A cells are able to initiate but not sustain a checkpoint response. We also report that γ-H2A is essential for the DNA damage checkpoint in crb2-T215A cells. Importantly, we show that inactivation of Cdc2 in γ-H2A-defective cells impairs Crb2-dependent signaling to the checkpoint kinase Chk1. These findings demonstrate that full Crb2 activity requires phosphorylation of threonine-215 by Cdc2. This regulation of Crb2 is independent of the histone modifications that are required for the hyperaccumulation of Crb2 at DSBs.

scholarly journals A Potential Phosphorylation Site for an A-Type Kinase in the Efg1 Regulator Protein Contributes to Hyphal Morphogenesis of Candida albicans

Genetics ◽  
2001 ◽  
Vol 157 (4) ◽  
pp. 1523-1530 ◽  
Author(s):  
Dirk P Bockmühl ◽  
Joachim F Ernst
Keyword(s):  
Candida Albicans ◽  
Phosphorylation Site ◽  
Human Fungal Pathogen ◽  
Hyphal Morphogenesis ◽  
Regulator Protein ◽  
Putative Phosphorylation Site ◽  
Hypha Formation ◽  
High Production ◽  
Signaling Components

Abstract Efg1p in the human fungal pathogen Candida albicans is a member of the conserved APSES class of proteins regulating morphogenetic processes in fungi. We have analyzed the importance for hyphal morphogenesis of a putative phosphorylation site for protein kinase A (PKA), threonine-206, within an Efg1p domain highly conserved among APSES proteins. Alanine substitution of T206, but not of the adjacent T207 and T208 residues, led to a block of hypha formation on solid and in liquid media, while a T206E exchange caused hyperfilamentation. The extent of the morphogenetic defect caused by the T206A mutation depended on hypha-induction conditions. Extragenous suppression of mutations in signaling components, including tpk2 and cek1 mutations, was achieved by wild-type- and T206E-, but not by the T206A-variant-encoding allele of EFG1. All muteins tested were produced at equal levels and at high production levels supported pseudohyphal formation. The results are consistent with a role of Efg1p as a central downstream component of a PKA-signaling pathway including Tpk2p or other PKA isoforms. Threonine-206 of Efg1p is essential as a putative phosphorylation target to promote hyphal induction by a subset of environmental cues.

Enhanced IgE response to Candida albicans in postoperative invasive candidiasis

1996 ◽  
Vol 26 (4) ◽  
pp. 452-460 ◽  
Author(s):  
J. SAVOLAINEN ◽  
A. RANTALA ◽  
M. NERMES ◽  
L. LEHTONEN ◽  
M. VIANDER
Keyword(s):  
Candida Albicans ◽  
Invasive Candidiasis ◽  
Ige Response

Existence of Candida albicans and microorganisms in denture stomatitis patients

1997 ◽  
Vol 24 (10) ◽  
pp. 788-790 ◽  
Author(s):  
Y. KULAK ◽  
A. ARIKAN ◽  
E. KAZAZOGLU
Keyword(s):  
Candida Albicans ◽  
Denture Stomatitis
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