Chapter 3 : Biosynthesis and Genetics of the Capsule

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Until the late 1940s, little was known about cryptococcal capsule composition or structure. Classically, the capsule is described as composed of glucuronoxylomannan (GXM), galactoxylomannan (GalXM), and mannoproteins, based on the original fractionation of shed polysaccharide material. Cell wall polymers are involved in capsule association with the cell, although they are not considered part of the capsule itself. Polysaccharide synthesis starts with the generation of precursor molecules, the most common being the activated sugars discovered by Leloir. A number of proteins involved in the synthesis of these precursors have been identified and studied in . This work has been facilitated by the fact that many of these enzymes are highly conserved in terms of sequence, as would be expected from the participation of activated sugar precursors in multiple synthetic pathways across biology. In support of a lumenal location for capsule synthesis, a conditional mutant generated in both serotypes A and D that is defective in vesicle targeting to the plasma membrane accumulates post-Golgi vesicles containing GXM. The conclusion from this study is that GXM is made within the classical secretory pathway, consistent with the requirement for nucleotide sugar transporters to achieve normal capsule synthesis.

Citation: Janbon G, Doering T. 2011. Biosynthesis and Genetics of the Capsule, p 27-41. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch3

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Image of FIGURE 1

The capsule. (a) The capsule as drawn by Curtis in 1896 ( ). (b) India ink negative staining demonstrates the capsule as a zone of exclusion surrounding the cell. (c) Immunofluorescence microscopy of cryptococci after labeling with an anti-GXM monoclonal antibody. (d) Capsule quelling reaction that occurs when is mixed with anti-GXM monoclonal antibody as visualized by differential interference contrast microscopy. Reprinted, with permission, from reference . (e) Quickfreeze deepetch image of the edge of a budding cell. The plasma membrane (upper left) is separated by the cell wall from the fibrous capsule meshwork (extending toward lower right). Both wall and capsule surround both the parent cell and the emerging bud. Reprinted, with permission, from the cover image associated with reference . Cryptococcal cell bodies are typically 4 to 6 μm in diameter; the capsule can range from undetectable to ~30 μm in radius.

Citation: Janbon G, Doering T. 2011. Biosynthesis and Genetics of the Capsule, p 27-41. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch3
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Image of FIGURE 2

The six structural reporter groups of GXM defined by Cherniak et al. ( ). Mannose residues (shaded circles) are α-1,3-linked; xylose (stars) and glucuronic acid residues (half-filled diamonds) shown above the mannose backbone are β-1,2-linked; xylose shown below the backbone is β-1,4-linked. All sugars are in pyranose form, and mannose acetylation is not shown. Shapes follow the recommendations of the (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=glyco2). Modified, with permission, from reference .

Citation: Janbon G, Doering T. 2011. Biosynthesis and Genetics of the Capsule, p 27-41. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch3
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Image of FIGURE 3

The GalXM (GXMGal) structure. (Top) The structure of GalXM proposed by Vaishnav et al. ( ). (Bottom) The upper structure as revised by Heiss et al. ( ). The side branches that occur on every second galactose of the polymer backbone may be substituted on all three residues, on only the more distal two residues, on only the proximal two residues, or not at all ( ). The two extreme cases are shown. Symbols are as in Fig. 2 , with galactose shown as open circles and linkages as indicated. Modified, with permission, from reference .

Citation: Janbon G, Doering T. 2011. Biosynthesis and Genetics of the Capsule, p 27-41. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch3
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Image of FIGURE 4

Stimuli that lead to an alteration of the capsule size. Additional factors have been studied for their ability to modulate capsule but have a less marked effect. See text for details.

Citation: Janbon G, Doering T. 2011. Biosynthesis and Genetics of the Capsule, p 27-41. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch3
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Image of FIGURE 5

Reactivity of different GXM-specific monoclonal antibodies with two strains representative of serotypes A and D. Serial twofold dilutions were spotted (starting with 3 × 10 cells on the first spot at the top of each lane) on a nitrocellulose membrane and probed with a panel of anti-GXM monoclonal antibodies (designated A through E). Reprinted, with permission, from reference .

Citation: Janbon G, Doering T. 2011. Biosynthesis and Genetics of the Capsule, p 27-41. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch3
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Image of FIGURE 6

Nucleotide sugar metabolism in A simplified reaction scheme, highlighting synthetic steps discussed in the text. Plain text indicates biosynthetic intermediates; bold text on arrows indicates enzyme names; other bold text indicates nucleotide sugars.

Citation: Janbon G, Doering T. 2011. Biosynthesis and Genetics of the Capsule, p 27-41. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch3
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Image of FIGURE 7

Cryptococcal vesicles. Two vesicle types observed in (Left) Vesicles of the classical secretory pathway fusing with the plasma membrane to release their cargo extracellularly. (Right) Vesicles formed within intracellular membrane-bound structures are released intact at the cell surface. Modified, with permission, from reference .

Citation: Janbon G, Doering T. 2011. Biosynthesis and Genetics of the Capsule, p 27-41. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch3
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Generic image for table

The Cap proteins

Citation: Janbon G, Doering T. 2011. Biosynthesis and Genetics of the Capsule, p 27-41. In Heitman J, Kozel T, Kwon-Chung K, Perfect J, Casadevall A (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555816858.ch3

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