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Review
. 2019 Jun 18:9:212.
doi: 10.3389/fcimb.2019.00212. eCollection 2019.

The cAMP/Protein Kinase a Pathway Regulates Virulence and Adaptation to Host Conditions in Cryptococcus neoformans

Affiliations
Review

The cAMP/Protein Kinase a Pathway Regulates Virulence and Adaptation to Host Conditions in Cryptococcus neoformans

Mélissa Caza et al. Front Cell Infect Microbiol. .

Abstract

Nutrient sensing is critical for adaptation of fungi to environmental and host conditions. The conserved cAMP/PKA signaling pathway contributes to adaptation by sensing the availability of key nutrients such as glucose and directing changes in gene expression and metabolism. Interestingly, the cAMP/PKA pathway in fungal pathogens also influences the expression of virulence determinants in response to nutritional and host signals. For instance, protein kinase A (PKA) in the human pathogen Cryptococcus neoformans plays a central role in orchestrating phenotypic changes, such as capsule elaboration and melanin production, that directly impact disease development. In this review, we focus first on insights into the role of the cAMP/PKA pathway in nutrient sensing for the model yeast Saccharomyces cerevisiae to provide a foundation for understanding the pathway in C. neoformans. We then discuss key features of cAMP/PKA signaling in C. neoformans including new insights emerging from the analysis of transcriptional and proteomic changes in strains with altered PKA activity and expression. Finally, we highlight recent studies that connect the cAMP/PKA pathway to cell surface remodeling and the formation of titan cells.

Keywords: HOG pathway; RIM pathway; cAMP/PKA pathway; capsule; cryptococcus; melanin; nutrient sensing; titan cells.

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Figures

Figure 1
Figure 1
The cAMP/PKA pathway in S. cerevisiae is dually activated by glucose via one mechanism involving glycolysis and the Ras-cAMP pathway proteins, and a second pathway of glucose sensing via the G-protein coupled receptor Gpr1. Glycolysis generates fructose-1,6-bis-phosphate which activates the Ras nucleotide exchange factor Cdc25 which in turn activates the GTPases Ras1 and Ras2. These proteins are inactivated by the GAPs Ira1 and Ira2. GTP-bound Ras1 and Ras2 promote cAMP production via activation of the adenylyl cyclase Cyr1. Gpr1 senses external glucose and acts via the GTPase Gpa2 to stimulate adenylyl cyclase Cyr1 to produce cAMP. Elevated cAMP promotes the dissociation of the catalytic (Tpk1, 2, 3) and regulatory (Bcy1) subunits of PKA leading to activation of PKA and downstream signaling. The phosphodiesterases Pde1 and Pde2 control intracellular cAMP levels by degradation. The subcellular distribution of Bcy1 is regulated by Yak1-dependent phosphorylation and oligomerization of D/D domains of Bcy1 results in a tetrameric structure of allowing interactions with putative AKAPs (i.e., Hsp60, Ira2, and Zds1). Transceptor proteins mediate PKA activation independent of changes in cAMP levels in response to ammonium (NH4+), amino acids (a.a.), phosphate (PO43−), sulfate (SO42−), iron (Fe), and zinc (Zn).
Figure 2
Figure 2
The cAMP/PKA pathway in C. neoformans contains core components including a G-protein coupled receptor Gpr4 [activated by methionine (Met)], a Gα protein Gpa1, a Gβ-like/RACK1 homolog Gib2, Gγ proteins Gpg1 and Gpg2, an RGS protein Crg2 and a GEF Ric8. These proteins along with CO2/HCO3- regulated by the carbonic anhydrase Can2 influence the activity of adenylyl cyclase Cac1 and the production of cAMP. Gib2 potentially promotes cAMP levels through the inhibition of Ras1 functions on Cac1. Unknown GPCRs and the tetraspanin protein Tsp2 sense external glucose and may participate in cAMP/PKA activation. The level of cAMP influences the dissociation of the catalytic (Pka1 and Pka2) and regulatory (Pkr1) subunits of PKA leading to activation of the kinase and downstream signaling. The phosphodiesterase Pde1 influences intracellular cAMP levels.
Figure 3
Figure 3
Connections between the cAMP/PKA pathway and virulence-related functions in C. neoformans. A variety of functions act at the cell surface to sense potential signals of relevance to mammalian hosts. These include iron sensing via the high affinity uptake system (Cft1-Cfo1), the ESCRT pathway and master iron regulator Cir1. The ESCRT pathway also participates in the pH-response RIM pathway. In response to alkaline pH, Rim101 is phosphorylated by PKA, cleaved by the protease Rim13, and relocalized to the nucleus where it regulates the expression of genes involved in cell wall remodeling. The cAMP/PKA and HOG pathways have opposing influences on capsule formation. In presence of glucose, cAMP activates PKA, which in turns phosphorylate the transcription factor Nrg1 that promotes expression of capsule synthesis gene and represses transcription of PBS2 and HOG1. Capsule enlargement requires increase mitochondrial oxidative phosphorylation activity, which generate increase of reactive oxygen species (ROS). ROS triggers Hog1 activation via its phosphorylation by Pbs2. Phosphorylated Hog1 translocates to the nucleus and reduces capsule biosynthesis by potentially accelerating mRNA degradation. The cAMP/PKA and RIM pathways as well as GPCR Gpr5 are required for titan cell elaboration.

References

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