Zinc-binding domain mediates pleiotropic functions of Yvh1 in Cryptococcus neoformans

J Microbiol. 2021 Jul;59(7):658-665. doi: 10.1007/s12275-021-1287-1. Epub 2021 Jul 1.

Abstract

Yvh1 is a dual-specificity phosphatase (DUSP) that is evolutionarily conserved in eukaryotes, including yeasts and humans. Yvh1 is involved in the vegetative growth, differentiation, and virulence of animal and plant fungal pathogens. All Yvh1 orthologs have a conserved DUSP catalytic domain at the N-terminus and a zinc-binding (ZB) domain with two zinc fingers (ZFs) at the C-terminus. Although the DUSP domain is implicated in the regulation of MAPK signaling in humans, only the ZB domain is essential for most cellular functions of Yvh1 in fungi. This study aimed to analyze the functions of the DUSP and ZB domains of Yvh1 in the human fungal pathogen Cryptococcus neoformans, whose Yvh1 (CnYvh1) contains a DUSP domain at the C-terminus and a ZB domain at the N-terminus. Notably, CnYvh1 has an extended internal domain between the two ZF motifs in the ZB domain. To elucidate the function of each domain, we constructed individual domain deletions and swapping strains by complementing the yvh1Δ mutant with wild-type (WT) or mutated YVH1 alleles and examined their Yvh1-dependent phenotypes, including growth under varying stress conditions, mating, and virulence factor production. Here, we found that the complementation of the yvh1Δ mutant with the mutated YVH1 alleles having two ZFs of the ZB domain, but not the DUSP and extended internal domains, restored the WT phenotypic traits in the yvh1Δ mutant. In conclusion, the ZB domain, but not the N-terminal DUSP domain, plays a pivotal role in the pathobiological functions of cryptococcal Yvh1.

Keywords: DUSP; fungal meningoencephalitis; virulence; zinc finger.

MeSH terms

  • Catalytic Domain
  • Cryptococcus neoformans / cytology
  • Cryptococcus neoformans / enzymology*
  • Cryptococcus neoformans / genetics
  • Cryptococcus neoformans / pathogenicity
  • Dual-Specificity Phosphatases / chemistry*
  • Dual-Specificity Phosphatases / metabolism*
  • Fungal Proteins / chemistry
  • Fungal Proteins / metabolism
  • Genetic Complementation Test
  • Melanins / biosynthesis
  • Mutation
  • Protein Binding
  • Protein Domains*
  • Urease / biosynthesis
  • Virulence Factors / biosynthesis
  • Zinc / metabolism*
  • Zinc Fingers

Substances

  • Fungal Proteins
  • Melanins
  • Virulence Factors
  • Dual-Specificity Phosphatases
  • Urease
  • Zinc