Abstract
ABSTRACTGlycans play diverse biological roles, ranging from structural and regulatory functions to mediating cellular interactions. For pathogens, they are also often required for virulence and survival in the host. In Cryptococcus neoformans, an opportunistic pathogen of humans, the acidic monosaccharide glucuronic acid (GlcA) is a critical component of multiple essential glycoconjugates. One of these glycoconjugates is the polysaccharide capsule, a major virulence factor that enables this yeast to modulate the host immune response and resist antimicrobial defenses. This allows cryptococci to colonize the lung and brain, leading to hundreds of thousands of deaths each year worldwide. Synthesis of most glycans, including capsule polysaccharides, occurs in the secretory pathway. However, the activated precursors for this process, nucleotide sugars, are made primarily in the cytosol. This topological problem is resolved by the action of nucleotide sugar transporters (NSTs). We discovered that Uut1 is the sole UDP-GlcA transporter in C. neoformans and is unique among NSTs for its narrow substrate range and high affinity for UDP-GlcA. Mutant cells with UUT1 deleted lack capsule polysaccharides and are highly sensitive to environmental stress. As a result, the deletion mutant is internalized and cleared by phagocytes more readily than wild-type cells are and is completely avirulent in mice. These findings expand our understanding of the requirements for capsule synthesis and cryptococcal virulence and elucidate a critical protein family.
Highlights
Glycans play diverse biological roles, ranging from structural and regulatory functions to mediating cellular interactions
We found no homologs of the transporters from Caenorhabditis elegans, Homo sapiens, or Drosophila melanogaster, we did find a predicted ortholog of the Arabidopsis thaliana transporter UUAT1 [33], which we termed Uut1 (CNAG_06230)
Similar to other nucleotide sugar transporters (NSTs), Uut1 is predicted to have an even number of transmembrane domains such that the N and C termini are on the same side of the membrane, likely in the cytosol
Summary
Glycans play diverse biological roles, ranging from structural and regulatory functions to mediating cellular interactions. In Cryptococcus neoformans, an opportunistic pathogen of humans, the acidic monosaccharide glucuronic acid (GlcA) is a critical component of multiple essential glycoconjugates One of these glycoconjugates is the polysaccharide capsule, a major virulence factor that enables this yeast to modulate the host immune response and resist antimicrobial defenses. IMPORTANCE Cryptococcus neoformans causes lethal meningitis in almost two hundred thousand immunocompromised patients each year Much of this fungal pathogen’s ability to resist host defenses and cause disease is mediated by carbohydrate structures, including a complex polysaccharide capsule around the cell. UDP-GlcA is a key biosynthetic precursor of cryptococcal polysaccharides These complex polymers associate with the cell wall to form the cryptococcal capsule, which provides a physical barrier against host immune defenses. GlcA comprises roughly 16% and 7% of the residues in GXM and GXMGal, respectively, and is responsible for their acidic nature
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