Tracy Nevitt

Throughout evolution, all organisms have harnessed the redox properties of copper (Cu) and iron (Fe) as a cofactor or structural determinant of proteins that perform critical functions in biology. At its most sobering stance to Earth's biome, Cu biochemistry allows photosynthetic organisms to harness solar energy and convert it into the organic energy that sustains the existence of all nonphotosynthetic life forms. The conversion of organic energy, in the form of nutrients that include… Show more

Throughout evolution, all organisms have harnessed the redox properties of copper (Cu) and iron (Fe) as a cofactor or structural determinant of proteins that perform critical functions in biology. At its most sobering stance to Earth's biome, Cu biochemistry allows photosynthetic organisms to harness solar energy and convert it into the organic energy that sustains the existence of all nonphotosynthetic life forms. The conversion of organic energy, in the form of nutrients that include carbohydrates, amino acids and fatty acids, is subsequently released during cellular respiration, itself a Cu-dependent process, and stored as ATP that is used to drive a myriad of critical biological processes such as enzyme-catalyzed biosynthetic processes, transport of cargo around cells and across membranes, and protein degradation. The life-supporting properties of Cu incur a significant challenge to cells that must not only exquisitely balance intracellular Cu concentrations, but also chaperone this redox-active metal from its point of cellular entry to its ultimate destination so as to avert the potential for inappropriate biochemical interactions or generation of damaging reactive oxidative species (ROS). In this review we chart the travels of Cu from the extracellular milieu of fungal and mammalian cells, its path within the cytosol as inferred by the proteins and ligands that escort and deliver Cu to intracellular organelles and protein targets, and its journey throughout the body of mammals. Show less

Candida glabrata is a major human pathogen due to its low susceptibility to conventional antifungal drugs and the dramatic increase in the number of immunocompromised individuals suffering from HIV AIDS, cancer, and diabetes. Iron overload is one of the most common genetically inherited diseases and reports suggest increased susceptibility of these patients to bacterial infection. The ability of microorganisms to obtain iron from their environment is a major determinant in their fitness and… Show more

Candida glabrata is a major human pathogen due to its low susceptibility to conventional antifungal drugs and the dramatic increase in the number of immunocompromised individuals suffering from HIV AIDS, cancer, and diabetes. Iron overload is one of the most common genetically inherited diseases and reports suggest increased susceptibility of these patients to bacterial infection. The ability of microorganisms to obtain iron from their environment is a major determinant in their fitness and hence in their ability to cause infectious disease. Here we demonstrate that the siderophore iron carrier is critical for C. glabrata survival after ingestion by mouse and human macrophage immune effector cells. Through the generation of macrophage models of human iron overload disease we demonstrate that ingested C. glabrata cells sense altered macrophage iron levels, and that the Sit1 siderophore-iron transporter functions as a critical determinant in the ability of C. glabrata to survive macrophage killing in a manner that is dependent on macrophage iron status. Our results reveal a role for siderophore-iron as a source of iron during C. glabrata infection, suggest additional therapeutic intervention strategies, and support a pivotal contribution for a common human iron overload disease in the mechanisms used for Fe acquisition in C. glabrata. Show less

Iron acquisition is a bona fide virulence determinant. The successful colonization of the mammalian host requires that microorganisms overcome the Fe aridity of this milieu in which the levels of circulating Fe are maintained exceedingly low both through the compartmentalization of this nutrient within cells as well as the tight binding of Fe to host circulating proteins and ligands. Microbes notoriously employ multiple strategies for high affinity Fe acquisition from the host that rely either… Show more

Iron acquisition is a bona fide virulence determinant. The successful colonization of the mammalian host requires that microorganisms overcome the Fe aridity of this milieu in which the levels of circulating Fe are maintained exceedingly low both through the compartmentalization of this nutrient within cells as well as the tight binding of Fe to host circulating proteins and ligands. Microbes notoriously employ multiple strategies for high affinity Fe acquisition from the host that rely either on the expression of receptors for host Fe-binding proteins and ligands, its reduction by cell surface reductases or the utilization of siderophores, small organic molecules with very high affinity for Fe(3+). This review will discuss the multiple mechanisms deployed by fungal pathogens in Fe acquisition focusing on the role of siderophore utilization in virulence as well as host immune strategies of iron withholding and emerging clinical evidence that human disorders of Fe homeostasis can act as modifiers of infectious disease. Show less

Copper (Cu) is a redox-active metal ion essential for most aerobic organisms. Cu serves as a catalytic and structural cofactor for enzymes that function in energy generation, iron acquisition, oxygen transport, cellular metabolism, peptide hormone maturation, blood clotting, signal transduction and a host of other processes. The inability to control Cu balance is associated with genetic diseases of overload and deficiency and has recently been tied to neurodegenerative disorders and fungal… Show more

Copper (Cu) is a redox-active metal ion essential for most aerobic organisms. Cu serves as a catalytic and structural cofactor for enzymes that function in energy generation, iron acquisition, oxygen transport, cellular metabolism, peptide hormone maturation, blood clotting, signal transduction and a host of other processes. The inability to control Cu balance is associated with genetic diseases of overload and deficiency and has recently been tied to neurodegenerative disorders and fungal virulence. The essential nature of Cu, the existence of human genetic disorders of Cu metabolism and the potential impact of Cu deposition in the environment have been driving forces for detailed investigations in microbial and eukaryotic model systems. Here we review recent advances in the identification and function of cellular and systemic molecules that drive Cu accumulation, distribution and sensing. Show less

The budding yeast Saccharomyces cerevisiae possesses a very flexible and complex programme of gene expression when exposed to a plethora of environmental insults. Therefore, yeast cell homeostasis control is achieved through a highly coordinated mechanism of transcription regulation involving several factors, each performing specific functions. Here, we present our current knowledge of the function of the yeast activator protein family, formed by eight basic-leucine zipper trans-activators… Show more

The budding yeast Saccharomyces cerevisiae possesses a very flexible and complex programme of gene expression when exposed to a plethora of environmental insults. Therefore, yeast cell homeostasis control is achieved through a highly coordinated mechanism of transcription regulation involving several factors, each performing specific functions. Here, we present our current knowledge of the function of the yeast activator protein family, formed by eight basic-leucine zipper trans-activators, which have been shown to play an important role in stress response. Show less

Exposure of Saccharomyces cerevisiae to several environmental insults, including conditions of oxidative, heavy metal, metalloid and heat stress, induces the expression of the YAP4 gene, previously shown to play a role in the response to hyperosmotic stress. Expression analyses in several mutant strains under pro-oxidant conditions have determined that YAP4 is regulated by the transactivators Yap1p and Msn2p. Mutation of either the Yap1p-response element (YRE), located at − 517 bp from the ATG,… Show more

Exposure of Saccharomyces cerevisiae to several environmental insults, including conditions of oxidative, heavy metal, metalloid and heat stress, induces the expression of the YAP4 gene, previously shown to play a role in the response to hyperosmotic stress. Expression analyses in several mutant strains under pro-oxidant conditions have determined that YAP4 is regulated by the transactivators Yap1p and Msn2p. Mutation of either the Yap1p-response element (YRE), located at − 517 bp from the ATG, or the most proximal stress response element (STRE) at −430 bp, is shown to strongly compromise YAP4 gene expression under these conditions. Furthermore, these two mutations in combination lead to a severe depletion of detectable mRNA levels, indicating interplay between the transcription factors Yap1p and Msn2p in the regulation of YAP4 transcription. Transcriptional activation of this gene reflects a concomitant increase in Yap4p protein levels that appear phosphorylated upon stress and negatively regulated by protein kinase A. Yap4p amino acid residues Ser89, Ser196 and Thr241 are shown to be required for protein phosphorylation and/or protein stability. Show less

Yeast, and especially Saccharomyces cerevisiae, are continuously exposed to rapid and drastic changes in their external milieu. Therefore, cells must maintain their homeostasis, which is achieved through a highly coordinated gene expression involving a plethora of transcription factors, each of them performing specific functions. Here, we discuss recent advances in our understanding of the function of the yeast activator protein family of eight basic-leucine zipper trans-activators that have… Show more

Yeast, and especially Saccharomyces cerevisiae, are continuously exposed to rapid and drastic changes in their external milieu. Therefore, cells must maintain their homeostasis, which is achieved through a highly coordinated gene expression involving a plethora of transcription factors, each of them performing specific functions. Here, we discuss recent advances in our understanding of the function of the yeast activator protein family of eight basic-leucine zipper trans-activators that have been implicated in various forms of stress response. Show less

Yeast, and especially Saccharomyces cerevisiae, are continuously exposed to rapid and drastic changes in their external milieu. Therefore, cells must maintain their homeostasis, which is achieved through a highly coordinated gene expression involving a plethora of transcription factors, each of them performing specific functions. Here, we discuss recent advances in our understanding of the function of the yeast activator protein family of eight basic-leucine zipper trans-activators that have… Show more

Yeast, and especially Saccharomyces cerevisiae, are continuously exposed to rapid and drastic changes in their external milieu. Therefore, cells must maintain their homeostasis, which is achieved through a highly coordinated gene expression involving a plethora of transcription factors, each of them performing specific functions. Here, we discuss recent advances in our understanding of the function of the yeast activator protein family of eight basic-leucine zipper trans-activators that have been implicated in various forms of stress response. Show less

YAP4, a member of the yeast activator protein (YAP) gene family, is induced in response to osmotic shock in the yeast Saccharomyces cerevisiae. The null mutant displays mild and moderate growth sensitivity at 0.4 M and 0.8 M NaCl respectively, a fact that led us to analyse YAP4 mRNA levels in the hog1 (high osmolarity glycerol) mutant. The data obtained show a complete abolition of YAP4 gene expression in this mutant, placing YAP4 under the HOG response pathway. YAP4 overexpression not only… Show more

YAP4, a member of the yeast activator protein (YAP) gene family, is induced in response to osmotic shock in the yeast Saccharomyces cerevisiae. The null mutant displays mild and moderate growth sensitivity at 0.4 M and 0.8 M NaCl respectively, a fact that led us to analyse YAP4 mRNA levels in the hog1 (high osmolarity glycerol) mutant. The data obtained show a complete abolition of YAP4 gene expression in this mutant, placing YAP4 under the HOG response pathway. YAP4 overexpression not only suppresses the osmosensitivity phenotype of the yap4 mutant but also relieves that of the hog1 mutant. Induction, under the conditions tested so far, requires the presence of the transcription factor Msn2p, but not of Msn4p, as YAP4 mRNA levels are depleted by at least 75% in the msn2 mutant. This result was further substantiated by the fact that full YAP4 induction requires the two more proximal stress response elements. Furthermore we find that GCY1, encoding a putative glycerol dehydrogenase, GPP2, encoding a NAD-dependent glycerol-3-phosphate phosphatase, and DCS2, a homologue to a decapping enzyme, have decreased mRNA levels in the yap4-deleted strain. Our data point to a possible, as yet not entirely understood, role of the YAP4 in osmotic stress response. Show less