Nicotinic Acid Limitation Regulates Silencing of
            <i>Candida</i>
            Adhesins During UTI

Domergue, Renee; Castaño, Irene; Peñas, Alejandro De Las; Zupancic, Margaret L.; Lockatell, Virginia; Hebel, J. Richard; Johnson, David E.; Cormack, Brendan P.

doi:10.1126/science.1108640

Cited by 231 publications

(252 citation statements)

References 24 publications

(2 reference statements)

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“…This is particularly relevant for the virulence of C. glabrata due to the subtelomere-based localization of EPA genes that are likely to be relieved of the telomere position effect in response to host environmental cues. Notably, transcriptional activation of EPA6, which is required for biofilm formation, has been shown to be regulated by niacin levels in the mouse model of urinary tract infection (47,50).…”

Section: Discussionmentioning

confidence: 99%

Identification of Components of the SUMOylation Machinery in Candida glabrata

Gujjula

Veeraiah

Kumar

et al. 2016

Journal of Biological Chemistry

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Regulation of protein function by reversible post-translational modification, SUMOylation, is widely conserved in the eukaryotic kingdom. SUMOylation is essential for cell growth, division, and adaptation to stress in most organisms, including fungi. As these are key factors in determination of fungal virulence, in this study, we have investigated the importance of SUMOylation in the human pathogen, Candida glabrata. We identified the enzymes involved in small ubiquitin-like modifier conjugation and show that there is strong conservation between Saccharomyces cerevisiae and C. glabrata. We demonstrate that SUMOylation is an essential process and that adaptation to stress involves changes in global SUMOylation in C. glabrata. Importantly, loss of the deSUMOylating enzyme CgUlp2 leads to highly reduced small ubiquitin-like modifier protein levels, and impaired growth, sensitivity to multiple stress conditions, reduced adherence to epithelial cells, and poor colonization of specific tissues in mice. Our study thus demonstrates a key role for protein SUMOylation in the life cycle and pathobiology of C. glabrata. SUMOylation, the covalent reversible conjugation of small ubiquitin-like modifier (SUMO) 5 polypeptide to lysine residues, often within the canonical consensus motif ⌿KXE (⌿ and X represent a hydrophobic amino acid and any amino acid, respectively) in target proteins, is a post-translational modification that plays a key regulatory role in several cellular processes, including transcription, protein homeostasis, stress response, and development (1, 2). The process of SUMO attachment consists of the following four steps: (i) processing of the ϳ10-kDa precursor SUMO peptide by SUMO-specific proteases to reveal a C-terminal diglycine motif in the mature SUMO; (ii) ATP-dependent activation of the processed SUMO through the thioester bond formation between the C-terminal glycine of SUMO and the catalytic cysteine of the E1-activating enzyme; (iii) transfer of the SUMO polypeptide from the E1 enzyme to a conserved cysteine in the E2-conjugating enzyme via a thioester linkage; and (iv) E3 ligase-mediated formation of an isopeptide bond between the C-terminal glycine of the SUMO and the ⑀-amino group of the lysine residue within the conserved sequence on the target protein (2, 3). Besides the precursor SUMO maturation, the SUMO-specific peptidases are also able to hydrolyze the isopeptide bond between SUMO and SUMO-modified proteins thereby rendering the SUMOylation process reversible.The SUMO polypeptide is ubiquitously present in all eukaryotes and highly conserved from yeast to mammals (1-3). SUMO modification of protein substrates has diverse functional consequences and range from increased protein stability to altered subcellular localization (1-3). Furthermore, deregulated expression of SUMOylation components has been implicated in several human diseases, including neurodegeneration, heart failure, cancer, diabetes, and infections by bacterial and viral pathogens (4, 5).In the yeast Saccharomyces cerevisiae,...

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Section: Discussionmentioning

confidence: 99%

Identification of Components of the SUMOylation Machinery in Candida glabrata

Gujjula

Veeraiah

Kumar

et al. 2016

Journal of Biological Chemistry

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“…C. glabrata is auxotrophic for NAD + . C. glabrata is able to grow in the bladder and urinary tract of patients because of its ability to synthesize NAD + from external metabolites such as nicotinamide ribosides (NRs) through the use of either the NR kinase (Nrk1) or the nicotinamidase Pnc1 (43,44). We found that nrk1 and pnc1 mutants are as virulent as control wild-type C. glabrata when introduced into MyD88 flies (Fig.…”

Section: Figure 3 Phagocytosis Of C Glabrata (C G) (A)mentioning

confidence: 93%

The Drosophila Toll Pathway Controls but Does Not Clear Candida glabrata Infections

Quintin

Asmar

Matskevich

et al. 2013

The Journal of Immunology

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The pathogenicity of Candida glabrata to patients remains poorly understood for lack of convenient animal models to screen large numbers of mutants for altered virulence. In this study, we explore the minihost model Drosophila melanogaster from the dual perspective of host and pathogen. As in vertebrates, wild-type flies contain C. glabrata systemic infections yet are unable to kill the injected yeasts. As for other fungal infections in Drosophila, the Toll pathway restrains C. glabrata proliferation. Persistent C. glabrata yeasts in wild-type flies do not appear to be able to take shelter in hemocytes from the action of the Toll pathway, the effectors of which remain to be identified. Toll pathway mutant flies succumb to injected C. glabrata. In this immunosuppressed background, cellular defenses provide a residual level of protection. Although both the Gram-negative binding protein 3 pattern recognition receptor and the Persephone protease-dependent detection pathway are required for Toll pathway activation by C. glabrata, only GNBP3, and not psh mutants, are susceptible to the infection. Both Candida albicans and C. glabrata are restrained by the Toll pathway, yet the comparative study of phenoloxidase activation reveals a differential activity of the Toll pathway against these two fungal pathogens. Finally, we establish that the high-osmolarity glycerol pathway and yapsins are required for virulence of C. glabrata in this model. Unexpectedly, yapsins do not appear to be required to counteract the cellular immune response but are needed for the colonization of the wild-type host.

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“…But why would a cell want to simply lower the expression of genes in this way, as opposed to simply having a weaker promoter for such genes? Perhaps subtelomeric genes regulated by Sir proteins in S. cereivisiae, like those in C. glabrata (De Las Peñas et al 2003;Domergue et al 2005;Ma et al 2009), are involved in regulating the transcription of genes that are necessary only under certain conditions. In support of this model, seven genes encoding metabolic enzymes increased in expression in all three sir mutants: CHA1, AAD15, IMD2, FDH1, THI5, VBA3, and PAU4.…”

Section: The Functional Significance Of Sir Proteins At Telomeresmentioning

confidence: 99%

“…This selective expression of one antigen over all the other antigen genes is maintained by the epigenetic silencing of all var copies except the expressed one (Tonkin et al 2009;Guizetti and Scherf 2013). Similarly, in Candida glabrata, the EPA adhesion genes essential for colonization of the host urinary tract are located in subtelomeric regions, and their expression is regulated by a Sir-protein-based silencing mechanism that is responsive to the differences in niacin concentration in the bloodstream vs. the urinary track (De Las Peñas et al 2003;Domergue et al 2005). In S. cerevisiae, genes encoding cell wall components and genes required for the metabolism of certain nutrients tend to be located in subtelomeric regions and are expressed specifically under certain stressful conditions (Ai et al 2002).…”

mentioning

confidence: 99%

The Chromatin and Transcriptional Landscape of NativeSaccharomyces cerevisiaeTelomeres and Subtelomeric Domains

2015

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Saccharomyces cerevisiae telomeres have been a paradigm for studying telomere position effects on gene expression. Telomere position effect was first described in yeast by its effect on the expression of reporter genes inserted adjacent to truncated telomeres. The reporter genes showed variable silencing that depended on the Sir2/3/4 complex. Later studies examining subtelomeric reporter genes inserted at natural telomeres hinted that telomere position effects were less pervasive than previously thought. Additionally, more recent data using the sensitive technology of chromatin immunoprecipitation and massively parallel sequencing (ChIP-Seq) revealed a discrete and noncontinuous pattern of coenrichment for all three Sir proteins at a few telomeres, calling the generality of these conclusions into question. Here we combined the ChIP-Seq of the Sir proteins with RNA sequencing (RNA-Seq) of messenger RNAs (mRNAs) in wild-type and in SIR2, SIR3, and SIR4 deletion mutants to characterize the chromatin and transcriptional landscape of all native S. cerevisiae telomeres at the highest achievable resolution. Most S. cerevisiae chromosomes had subtelomeric genes that were expressed, with only 6% of subtelomeric genes silenced in a SIR-dependent manner. In addition, we uncovered 29 genes with previously unknown cell-type-specific patterns of expression. These detailed data provided a comprehensive assessment of the chromatin and transcriptional landscape of the subtelomeric domains of a eukaryotic genome.KEYWORDS Sir complex; telomeres; ChIP-Seq; RNA-Seq; mating-type regulation T ELOMERES are specialized structures at the ends of eukaryotic chromosomes that are critical for various biological functions. Telomeres bypass the problem of replicating the ends of linear DNA, protect chromosome ends from exonucleases and nonhomologous end joining, prevent the linear DNA ends from activating a DNA-damage checkpoint, and exhibit suppressed recombination [reviewed in Wellinger and Zakian (2012)]. In Saccharomyces cerevisiae, telomeres are composed of three sequence features: telomeric repeats, which consist of 300 6 75 bp of (TG 1-3 ) n repeated units produced by telomerase; X elements; and Y9 elements, which contain an ORF for a putative helicase gene. The X elements are subdivided into a core X [consisting of an autonomously replicating sequence (ARS) consensus sequence and an Abf1-binding site] and subtelomeric repeats that have variable numbers of repeated units containing a binding site for Tbf1 (Louis 1995). All telomeres contain telomeric repeats plus an X element, and about half of S. cerevisiae's 32 telomeres also contain a Y9 element (X-Y9 telomeres). X-only telomeres contain an X element but not a Y9 element. Unlike the Y9 elements, the telomeric repeats and X elements are bound by proteins that are critical for maintenance of telomeres. Rap1 binds the TG 1-3 telomeric repeats and recruits the Sir2/3/4 protein complex, the trio of heterochromatin structural proteins critical for repression of the silent mating ...

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Nicotinic Acid Limitation Regulates Silencing of Candida Adhesins During UTI

Cited by 231 publications

References 24 publications

Identification of Components of the SUMOylation Machinery in Candida glabrata

Identification of Components of the SUMOylation Machinery in Candida glabrata

The Drosophila Toll Pathway Controls but Does Not Clear Candida glabrata Infections

The Chromatin and Transcriptional Landscape of NativeSaccharomyces cerevisiaeTelomeres and Subtelomeric Domains

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