Biosynthesis and Genetics of the Cryptococcus Capsule

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 Cryptococcus neoformans. 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.