Cyclic AMP-Dependent Protein Kinase Catalytic Subunits Have Divergent Roles in Virulence Factor Production in Two Varieties of the Fungal Pathogen
            <i>Cryptococcus neoformans</i>

Hicks, Julie K.; D’Souza, Cletus A.; Cox, Gary M.; Heitman, Joseph

doi:10.1128/ec.3.1.14-26.2004

Cited by 90 publications

(113 citation statements)

References 77 publications

(82 reference statements)

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“…Intriguingly, research has shown that these two protein kinases possess distinct roles in strains of different serotypes. Pka1 plays a predominant role in cAMP signaling in serotype A strains, regulating melanin and capsule production and virulence (10), whereas Pka2 plays a predominant role in serotype D strains, regulating melanin and capsule production (225). Surprisingly, PKA is not required for virulence in serotype D strains, as measured with a murine model of cryptococcosis (225).…”

Section: Major Morphogenetic Signaling Cascadesmentioning

confidence: 99%

“…Pka1 plays a predominant role in cAMP signaling in serotype A strains, regulating melanin and capsule production and virulence (10), whereas Pka2 plays a predominant role in serotype D strains, regulating melanin and capsule production (225). Surprisingly, PKA is not required for virulence in serotype D strains, as measured with a murine model of cryptococcosis (225). Furthermore, in serotype A strains, the loss of the PKA regulatory subunit Pkr1 results in the overproduction of capsule, hypervirulence, and the suppression of phenotypes observed for a gpa1 mutant (160).…”

Section: Major Morphogenetic Signaling Cascadesmentioning

confidence: 99%

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Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

492

547

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SUMMARY Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans , several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus , which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans , C. neoformans , and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

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Section: Major Morphogenetic Signaling Cascadesmentioning

confidence: 99%

Section: Major Morphogenetic Signaling Cascadesmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

492

547

View full text Add to dashboard Cite

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“…C. neoformans contains a single adenylyl cyclase, Cac1 (4). cAMP signaling from Cac1 is bifurcated into two PKA catalytic subunits, Pka1 and Pka2, whose activation is inhibited by the regulatory subunit Pkr1 (9,30). Notably, Pka1 plays a predominant role in cAMP signaling in the serotype A C. neoformans H99 strain background, whereas Pka2 does so in the serotype D C. neoformans JEC21 strain (30).…”

mentioning

confidence: 99%

“…cAMP signaling from Cac1 is bifurcated into two PKA catalytic subunits, Pka1 and Pka2, whose activation is inhibited by the regulatory subunit Pkr1 (9,30). Notably, Pka1 plays a predominant role in cAMP signaling in the serotype A C. neoformans H99 strain background, whereas Pka2 does so in the serotype D C. neoformans JEC21 strain (30). Interestingly, the low-affinity phosphodiesterase Pde1, but not the high-affinity phosphodiesterase Pde2, plays a key role in negatively regulating the cAMP pathway in C. neoformans (29) (see Fig.…”

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confidence: 99%

Comparative Transcriptome Analysis Reveals Novel Roles of the Ras and Cyclic AMP Signaling Pathways in Environmental Stress Response and Antifungal Drug Sensitivity in Cryptococcus neoformans

et al. 2010

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The cyclic AMP (cAMP) pathway plays a central role in the growth, differentiation, and virulence of pathogenic fungi, including Cryptococcus neoformans. Three upstream signaling regulators of adenylyl cyclase (Cac1), Ras, Aca1, and Gpa1, have been demonstrated to control the cAMP pathway in C. neoformans, but their functional relationship remains elusive. We performed a genome-wide transcriptome analysis with a DNA microarray using the ras1⌬, gpa1⌬, cac1⌬, aca1⌬, and pka1⌬ pka2⌬ mutants. The aca1⌬, gpa1⌬, cac1⌬, and pka1⌬ pka2⌬ mutants displayed similar transcriptome patterns, whereas the ras1⌬ mutant exhibited transcriptome patterns distinct from those of the wild type and the cAMP mutants. Interestingly, a number of environmental stress response genes are modulated differentially in the ras1⌬ and cAMP mutants. In fact, the Ras signaling pathway was found to be involved in osmotic and genotoxic stress responses and the maintenance of cell wall integrity via the Cdc24-dependent signaling pathway. Notably, the Ras and cAMP mutants exhibited hypersensitivity to a polyene drug, amphotericin B, without showing effects on ergosterol biosynthesis, which suggested a novel method of antifungal combination therapy. Among the cAMP-dependent gene products that we characterized, two small heat shock proteins, Hsp12 and Hsp122, were found to be involved in the polyene antifungal drug susceptibility of C. neoformans.

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“…In Cryptococcus neoformans, which causes fungal meningoencephalitis, disruption of an AC gene (CAC1) disables the production of two major virulence factors without affecting viability: the antiphagocytic polysaccharide capsule, which also interferes with normal functions of host cells, and melanin, which acts as an antioxidant (2). The virulence of C. neoformans also is significantly attenuated by disrupting or mutating other genes that function in the cAMP signaling pathway, such as GPA1 (G␣ protein), PKA1 (PKA catalytic subunit), and ACA1 (AC-associated protein) (1,4,20,29). In the rice blast fungus Magnaporthe grisea, deletion of the AC gene (MAC1) abolishes the ability of cells to form appressoria for penetration of plant hosts and reduces growth (17).…”

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confidence: 99%

Genome-Wide Transcriptional Profiling of the Cyclic AMP-Dependent Signaling Pathway during Morphogenic Transitions of Candida albicans

et al. 2007

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Candida albicans is an opportunistic human fungal pathogen that causes systemic candidiasis as well as superficial mucosal candidiasis. In response to the host environment, C. albicans transitions between yeast and hyphal forms. In particular, hyphal growth is important in facilitating adhesion and invasion of host tissues, concomitant with the expression of various hypha-specific virulence factors. In previous work, we showed that the cyclic AMP (cAMP) signaling pathway plays a crucial role in morphogenic transitions and virulence of C. albicans by studying genes encoding adenylate cyclase-associated protein ( Here, microarrays were probed with RNA from strains with hypoactive (cap1/cap1 null mutant), hyperactive (pde2/pde2 null mutant), and wild-type cAMP signaling pathways to provide insight into the molecular mechanisms of virulence that are regulated by cAMP and that are related to the morphogenesis of C. albicans. Genes controlling metabolic specialization, cell wall structure, ergosterol/lipid biosynthesis, and stress responses were modulated by cAMP during hypha formation. Phenotypic traits predicted to be regulated by cAMP from the profiling results correlated with the relative strengths of the mutants when tested for resistance to azoles and subjected to heat shock stress and oxidative/nitrosative stress. The results from this study provide important insights into the role of the cAMP signaling pathway not only in morphogenic transitions of C. albicans but also for adaptation to stress and for survival during host infections.

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Cyclic AMP-Dependent Protein Kinase Catalytic Subunits Have Divergent Roles in Virulence Factor Production in Two Varieties of the Fungal Pathogen Cryptococcus neoformans

Cited by 90 publications

References 77 publications

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Comparative Transcriptome Analysis Reveals Novel Roles of the Ras and Cyclic AMP Signaling Pathways in Environmental Stress Response and Antifungal Drug Sensitivity in Cryptococcus neoformans

Genome-Wide Transcriptional Profiling of the Cyclic AMP-Dependent Signaling Pathway during Morphogenic Transitions of Candida albicans

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