scholarly journals Ppg1, a PP2A-Type Protein Phosphatase, Controls Filament Extension and Virulence in Candida albicans

2014 ◽  
Vol 13 (12) ◽  
pp. 1538-1547 ◽  
Author(s):  
Mohammad T. Albataineh ◽  
Anna Lazzell ◽  
Jose L. Lopez-Ribot ◽  
David Kadosh
Keyword(s):  
Signal Transduction ◽  
Candida Albicans ◽  
Protein Phosphatase ◽  
Target Genes ◽  
Filamentous Growth ◽  
Fine Tuning ◽  
Signal Transduction Pathways ◽  
Content Type ◽  
Human Fungal Pathogen ◽  
Epistasis Analysis

ABSTRACT Candida albicans , a major human fungal pathogen, is the primary cause of invasive candidiasis in a wide array of immunocompromised patients. C. albicans virulence requires the ability to undergo a reversible morphological transition from yeast to filaments in response to a variety of host environmental cues. These cues are sensed by the pathogen and activate multiple signal transduction pathways to induce filamentation. Reversible phosphorylation events are critical for regulation of many of these pathways. While a variety of protein kinases are known to function as components of C. albicans filamentous growth signal transduction pathways, considerably little is known about the role of phosphatases. Here we demonstrate that PPG1 , encoding a putative type 2A-related protein phosphatase, is important for C. albicans filament extension, invasion, and virulence in a mouse model of systemic candidiasis. PPG1 is also important for downregulation of NRG1 , a key transcriptional repressor of C. albicans filamentous growth, and is shown to affect the expression of several filament-specific target genes. An epistasis analysis suggests that PPG1 controls C. albicans filamentation via the cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway. We demonstrate that Ppg1 possesses phosphatase activity and that a ppg1 catalytic mutant shows nearly equivalent filamentation, invasion, and virulence defects compared to those of a ppg1 Δ/Δ strain. Overall, our results suggest that phosphatases, such as Ppg1, play critical roles in controlling and fine-tuning C. albicans filament extension and virulence as well as signal transduction pathways, transcriptional regulators, and target genes associated with these processes.

scholarly journals TUP1, CPH1 and EFG1 Make Independent Contributions to Filamentation in Candida albicans

Genetics ◽  
2000 ◽  
Vol 155 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Burkhard R Braun ◽  
Alexander D Johnson
Keyword(s):  
Candida Albicans ◽  
Environmental Conditions ◽  
Target Genes ◽  
Single Cells ◽  
Filamentous Growth ◽  
Surface Proteins ◽  
Pathway Expression ◽  
Separate Pathway ◽  
The Common ◽  
Growth Pathway

Abstract The common fungal pathogen, Candida albicans, can grow either as single cells or as filaments (hyphae), depending on environmental conditions. Several transcriptional regulators have been identified as having key roles in controlling filamentous growth, including the products of the TUP1, CPH1, and EFG1 genes. We show, through a set of single, double, and triple mutants, that these genes act in an additive fashion to control filamentous growth, suggesting that each gene represents a separate pathway of control. We also show that environmentally induced filamentous growth can occur even in the absence of all three of these genes, providing evidence for a fourth regulatory pathway. Expression of a collection of structural genes associated with filamentous growth, including HYR1, ECE1, HWP1, ALS1, and CHS2, was monitored in strains lacking each combination of TUP1, EFG1, and CPH1. Different patterns of expression were observed among these target genes, supporting the hypothesis that these three regulatory proteins engage in a network of individual connections to downstream genes and arguing against a model whereby the target genes are regulated through a central filamentous growth pathway. The results suggest the existence of several distinct types of filamentous forms of C. albicans, each dependent on a particular set of environmental conditions and each expressing a unique set of surface proteins.

scholarly journals Spitzenkörper, Exocyst, and Polarisome Components in Candida albicans Hyphae Show Different Patterns of Localization and Have Distinct Dynamic Properties

2010 ◽  
Vol 9 (10) ◽  
pp. 1455-1465 ◽  
Author(s):  
Laura A. Jones ◽  
Peter E. Sudbery
Keyword(s):  
Candida Albicans ◽  
Cell Surface ◽  
Fluorescence Recovery After Photobleaching ◽  
Dynamic Properties ◽  
Secretory Vesicles ◽  
Content Type ◽  
Human Fungal Pathogen ◽  
Actin Cables ◽  
Cytochalasin A ◽  
Subapical Region

ABSTRACT During the extreme polarized growth of fungal hyphae, secretory vesicles are thought to accumulate in a subapical region called the Spitzenkörper. The human fungal pathogen Candida albicans can grow in a budding yeast or hyphal form. When it grows as hyphae, Mlc1 accumulates in a subapical spot suggestive of a Spitzenkörper-like structure, while the polarisome components Spa2 and Bud6 localize to a surface crescent. Here we show that the vesicle-associated protein Sec4 also localizes to a spot, confirming that secretory vesicles accumulate in the putative C. albicans Spitzenkörper. In contrast, exocyst components localize to a surface crescent. Using a combination of fluorescence recovery after photobleaching (FRAP) and fluorescence loss in photobleaching (FLIP) experiments and cytochalasin A to disrupt actin cables, we showed that Spitzenkörper-located proteins are highly dynamic. In contrast, exocyst and polarisome components are stably located at the cell surface. It is thought that in Saccharomyces cerevisiae exocyst components are transported to the cell surface on secretory vesicles along actin cables. If each vesicle carried its own complement of exocyst components, then it would be expected that exocyst components would be as dynamic as Sec4 and would have the same pattern of localization. This is not what we observe in C. albicans. We propose a model in which a stream of vesicles arrives at the tip and accumulates in the Spitzenkörper before onward delivery to the plasma membrane mediated by exocyst and polarisome components that are more stable residents of the cell surface.

scholarly journals Transcriptional Regulators Cph1p and Efg1p Mediate Activation of the Candida albicans Virulence Gene SAP5 during Infection

2002 ◽  
Vol 70 (2) ◽  
pp. 921-927 ◽  
Author(s):  
Peter Staib ◽  
Marianne Kretschmar ◽  
Thomas Nichterlein ◽  
Herbert Hof ◽  
Joachim Morschhäuser
Keyword(s):  
Signal Transduction ◽  
Candida Albicans ◽  
Genetic Recombination ◽  
Hyphal Growth ◽  
Transcriptional Regulators ◽  
Infected Tissue ◽  
Mitogen Activated Protein Kinase ◽  
Signal Transduction Pathways ◽  
Aspartic Proteinases

ABSTRACT The opportunistic fungal pathogen Candida albicans can cause superficial as well as systemic infections. Successful adaptation to the different host niches encountered during infection requires coordinated expression of various virulence traits, including the switch between yeast and hyphal growth forms and secretion of aspartic proteinases. Using an in vivo expression technology that is based on genetic recombination as a reporter of gene activation during experimental candidiasis in mice, we investigated whether two signal transduction pathways controlling hyphal growth, a mitogen-activated protein kinase cascade ending in the transcriptional activator Cph1p and a cyclic AMP-dependent regulatory pathway that involves the transcription factor Efg1p, also control expression of the SAP5 gene, which encodes one of the secreted aspartic proteinases and is induced by host signals soon after infection. Our results show that both transcriptional regulators are important for SAP5 activation in vivo. SAP5 expression was reduced in a cph1 mutant, although filamentous growth in infected tissue was not detectably impaired. SAP5 expression was also reduced, but not eliminated, in an efg1 null mutant, although this strain grew exclusively in the yeast form in infected tissue, demonstrating that in contrast to in vitro conditions, SAP5 activation during infection does not depend on growth of C. albicans in the hyphal form. In a cph1 efg1 double mutant, however, SAP5 expression in infected mice was almost completely eliminated, suggesting that the two signal transduction pathways are important for SAP5 expression in vivo. The avirulence of the cph1 efg1 mutant seemed to be caused not only by the inability to form hyphae but also by a loss of expression of additional virulence genes in the host.

scholarly journals Protection from Systemic Candida albicans Infection by Inactivation of the Sts Phosphatases

2014 ◽  
Vol 83 (2) ◽  
pp. 637-645 ◽  
Author(s):  
Shamoon Naseem ◽  
David Frank ◽  
James B. Konopka ◽  
Nick Carpino
Keyword(s):  
Candida Albicans ◽  
Fungal Pathogen ◽  
Fungal Growth ◽  
Systemic Infection ◽  
Content Type ◽  
Host Immune Responses ◽  
Human Fungal Pathogen ◽  
Rapid Induction ◽  
Inflammatory Damage ◽  
Functional Inactivation

The human fungal pathogenCandida albicanscauses invasive candidiasis, characterized by fatal organ failure due to disseminated fungal growth and inflammatory damage. Thesuppressor ofTCRsignaling 1 (Sts-1) and Sts-2 are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic cell lineages, including T lymphocytes, mast cells, and platelets. Functional inactivation of both Sts enzymes leads to profound resistance to systemic infection byC. albicans, such that greater than 80% of mice lacking Sts-1 and -2 survive a dose ofC. albicans(2.5 × 105CFU/mouse) that is uniformly lethal to wild-type mice within 10 days. Restriction of fungal growth within the kidney occurs by 24 h postinfection in the mutant mice. This occurs without induction of a hyperinflammatory response, as evidenced by the decreased presence of leukocytes and inflammatory cytokines that normally accompany the antifungal immune response. Instead, the absence of the Sts phosphatases leads to the rapid induction of a unique immunological environment within the kidney, as indicated by the early induction of a proinflammatory cytokine (CXL10). Mice lacking either Sts enzyme individually display an intermediate lethality phenotype. These observations identify an opportunity to optimize host immune responses toward a deadly fungal pathogen.

scholarly journals Candida albicans Ume6, a Filament-Specific Transcriptional Regulator, Directs Hyphal Growth via a Pathway Involving Hgc1 Cyclin-Related Protein

2010 ◽  
Vol 9 (9) ◽  
pp. 1320-1328 ◽  
Author(s):  
Patricia L. Carlisle ◽  
David Kadosh
Keyword(s):  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Constitutive Expression ◽  
Transcriptional Regulator ◽  
Hyphal Growth ◽  
Related Protein ◽  
Content Type ◽  
Epistasis Analysis ◽  
Dependent Inactivation ◽  
Hyphal Formation

ABSTRACT The ability of Candida albicans, the most common human fungal pathogen, to transition from yeast to hyphae is essential for pathogenicity. While a variety of transcription factors important for filamentation have been identified and characterized, links between transcriptional regulators of C. albicans morphogenesis and molecular mechanisms that drive hyphal growth are not well defined. We have previously observed that constitutive expression of UME6, which encodes a filament-specific transcriptional regulator, is sufficient to direct hyphal growth in the absence of filament-inducing conditions. Here we show that HGC1, encoding a cyclin-related protein necessary for hyphal growth under filament-inducing conditions, is specifically important for agar invasion, hyphal extension, and formation of true septa in response to constitutive UME6 expression under non-filament-inducing conditions. HGC1-dependent inactivation of Rga2, a Cdc42 GTPase activating protein (GAP), also appears to be important for these processes. In response to filament-inducing conditions, HGC1 is induced prior to UME6 although UME6 controls the level and duration of HGC1 expression, which are likely to be important for hyphal extension. Interestingly, an epistasis analysis suggests that UME6 and HGC1 play distinct roles during early filament formation. These findings establish a link between a key regulator of filamentation and a downstream mechanism important for hyphal formation. In addition, this study demonstrates that a strain expressing constitutive high levels of UME6 provides a powerful strategy to specifically dissect downstream mechanisms important for hyphal development in the absence of complex filament-inducing conditions.

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