The Ess1 prolyl isomerase is dispensable for growth but required for virulence in Crytococcus neoformans

Cryptococcus neoformans an important human fungal pathogen that also serves as a model for studies of fungal pathogenesis. C. neoformans contains several genes encoding peptidyl-prolyl cis/trans isomerases (PPlases), enzymes that catalyse changes in the folding and conformation of target proteins. Three distinct classes of PPlases have been identified: cyclophilins, FK506-binding proteins (FKBPs) and parvulins. This paper reports the cloning and characterization of ESS1, which is believed to be the first (and probably only) parvulin-class PPlase in C. neoformans. It is shown that ESS1 from C. neoformans is structurally and functionally homologous to ESS1 from Saccharomyces cerevisiae, which encodes an essential PPlase that interacts with RNA polymerase II and plays a role in transcription. In C. neoformans, ESS1 was found to be dispensable for growth, haploid fruiting and capsule formation. However, ESS1 was required for virulence in a murine model of cryptococcosis. Loss of virulence might have been due to the defects in melanin and urease production observed in ess1 mutants, or to defects in transcription of as-yet-unidentified virulence genes. The fact that Ess1 is not essential in C. neoformans suggests that, in this organism, some of its functions might be subsumed by other prolyl isomerases, in particular, cyclophilins Cpa1 or Cpa2. This is supported by the finding that ess1 mutants were hypersensitive to cyclosporin A. C. neoformans might therefore be a useful organism in which to investigate crosstalk among different families of prolyl isomerases.