Chapter 17 : Signaling Cascades and Enzymes as Virulence Factors

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Signal transduction cascades are utilized by all organisms to convey signals perceived at the cell surface to effectors within the cell. These enzymatic signaling cascades are important in the pathogenesis of many infections, including cryptococcosis. This chapter summarizes the significance and functional interactions involved in the cell wall integrity, phospholipase, and calcineurin signaling pathways for the establishment of virulence. The fungal Plc enzymes referred to in this review preferentially hydrolyze phosphatidylinositol (PI)-based substrates within the cryptococcal cell and affect multiple cellular functions, including the secretion of (phospholipase B ) Plb1. It was found that the Plb1 MW could be as high as 125 kDa due to extensive asparagine N-linked glycosylation, which is responsible for at least 30% of the MW of Plb1 and essential for its activity. It was recently demonstrated that PI-PLC1 (Plc1) regulates cryptococcal virulence, acting in part through interactions with the Pkc/Mpk1 cell wall integrity pathway. In contrast to Plcs from higher eukaryotes, Plcs from the parasite preferentially hydrolyze the glycosylphosphatidylinositol (GPI) anchor of variant surface glycoprotein or GPI biosynthetic intermediates, in addition to PI, but not the phosphorylated intermediates, despite their localization to the peripheral cytoplasmic face of intracellular vesicles. Metabolic labeling studies performed in implicated a Plc enzyme and a secondary-acting protease in hydrolysis of the GPI anchor of certain proteins in the plasma membrane, resulting in their subsequent localization in the cell wall. ScPlc1, the only Plc1 in , like CnPlc1, lacks a secretory signal leader peptide.

Citation: Fox D, Djordjevic J, Sorrell T. 2011. Signaling Cascades and Enzymes as Virulence Factors, p 217-234. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch17
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Image of FIGURE 1

Site of attack of phospholipases on a phospholipid. R1 and R2 are fatty acid chains; X is a head group. Phospholipase A hydrolyzes the fatty acyl ester bond at the position of the phospholipid to form a 2-acyl phospholipid (lysophospholipid) and a free fatty acid. Phospholipase A cleaves the fatty acyl ester bond at the position of this molecule, resulting in the formation of a lysophospholipid. Phospholipase B (PLB) catalyzes the simultaneous hydrolysis of fatty acids from both the and position of the phospholipid. Phospholipase C cleaves the phosphodiester bond in the phospholipid backbone to form 1,2-diacylglycerol and a phosphorylated head group. Phospholipase D removes the head group from the phospholipid, forming phosphatidic acid. Plb1 has the strongest preference for PC, where the head group (X) is choline, and shows weaker preference for PI, phosphatidylethanolamine, and phosphatidylserine, where the head groups are inositol, ethanolamine, and serine, respectively. Adapted from reference .

Citation: Fox D, Djordjevic J, Sorrell T. 2011. Signaling Cascades and Enzymes as Virulence Factors, p 217-234. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch17
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Image of FIGURE 2

Possible surface release mechanisms for GPI-anchored proteins. (A) Model of a GPI-anchored protein showing potential sites of GPI anchor hydrolysis at the membrane. E, ethanolamine; P, phosphate; M, mannose; G, glucosamine; I, inositol. Arrows indicate potential cleavage sites (protein release mechanisms). Mannose residues from top to bottom are α-1,2-, 1,6-, and 1,4-linked. The PI moiety is attached to a diacyl group embedded in the membrane. The site of YW3548 inhibition of GPI anchor biosynthesis (prior to GPI anchor addition to the protein) is also shown. (B) Organization of the fungal cell wall. Potential sites of β-1,3-glucanase cleavage, releasing GPI-anchored proteins linked to β-1,6-glucan polymer, are indicated (in this case the GPI-anchored protein was released from the membrane by α-mannosidase). Modified from reference , with permission from Landes Bioscience.

Citation: Fox D, Djordjevic J, Sorrell T. 2011. Signaling Cascades and Enzymes as Virulence Factors, p 217-234. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch17
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Image of FIGURE 3

Comparison of the predicted Plc/PI-PLC protein motifs. (A) Plc1 proteins in all three yeast species and in the human PLC-δ4 isoform contain an X and Y catalytic domain and a C2 “calcium-binding” domain. is the only yeast species with an EFhand domain. (B) Plc2 proteins from and , the Plc3 protein from , and Plcs from and all contain only an X catalytic domain. Published with permission from Blackwell Publishing Ltd. ( ).

Citation: Fox D, Djordjevic J, Sorrell T. 2011. Signaling Cascades and Enzymes as Virulence Factors, p 217-234. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch17
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Image of FIGURE 4

Model depicting the functional linkages of the Pkc1/Mpk1, phospholipase, and calcineurin signaling pathways in the regulation of cell wall integrity in . Phospholipase C (Plc1) signaling mediates cell wall integrity and high-temperature growth through activation of the Pkc1/Mpk1 and calcineurin pathways. The phospholipid-binding protein Cts1 may direct communication between Plc1 and calcineurin signaling pathways. The calcineurin regulator and effector Rcn1 may facilitate some aspects of calcineurin activity by modulation of calcineurin substrate specificity, while Kre6 may serve as a possible calcineurin substrate and regulator of β-glucan synthesis. The putative cell wall/membrane sensor of cell wall integrity is depicted as WSC. PI, phosphatidylinositol; DAG, 1,2-diacylglycerol; IP, inositol 1,4,5-triphosphate. Adapted from references .

Citation: Fox D, Djordjevic J, Sorrell T. 2011. Signaling Cascades and Enzymes as Virulence Factors, p 217-234. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch17
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Image of FIGURE 5

Calcineurin catalytic subunit Cna1 interacts with the predicted cytosolic domain of Kre6. (A) Isogenic two-hybrid reporter strains expressing calcineurin B (Y190) or lacking calcineurin B (SMY7-7) were cotransformed with plasmids expressing the Gal4 DNA-binding domain alone or fused to calcineurin A: full length (CNA1) or the C-terminal tail (CNA1-CT) and the Gal4 activation domain alone or fused to the Kre6 cytoplasmic domain (KRE6-pS) (alleles listed on axis). Interaction values are shown in Miller units. (B) Two-hybrid analysis to map the Kre6 binding region within calcineurin A. Open reading frame (ORF) length is shown in amino acid residues. The shaded boxes indicate the catalytic, calcineurin B-binding (B), calmodulin-binding (Cm), and autoinhibitory (AID) domains of calcineurin A.

Citation: Fox D, Djordjevic J, Sorrell T. 2011. Signaling Cascades and Enzymes as Virulence Factors, p 217-234. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch17
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