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

Abstract

Cryptococcus neoformansis an important human fungal pathogen that also serves as a model for studies of fungal pathogenesis.C. neoformanscontains several genes encoding peptidyl-prolylcis/transisomerases (PPIases), enzymes that catalyse changes in the folding and conformation of target proteins. Three distinct classes of PPIases have been identified: cyclophilins, FK506-binding proteins (FKBPs) and parvulins. This paper reports the cloning and characterization ofESS1, which is believed to be the first (and probably only) parvulin-class PPIase inC. neoformans. It is shown thatESS1fromC. neoformansis structurally and functionally homologous toESS1fromSaccharomyces cerevisiae, which encodes an essential PPIase that interacts with RNA polymerase II and plays a role in transcription. InC. neoformans,ESS1was found to be dispensable for growth, haploid fruiting and capsule formation. However,ESS1was 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 iness1mutants, or to defects in transcription of as-yet-unidentified virulence genes. The fact that Ess1 is not essential inC. neoformanssuggests 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 thatess1mutants were hypersensitive to cyclosporin A.C. neoformansmight therefore be a useful organism in which to investigate crosstalk among different families of prolyl isomerases.