Identification of a Zds-like gene ZDS3 as a new mediator of stress resistance, capsule formation and virulence of the human pathogenic yeast Cryptococcus neoformans

The fungal Zds proteins are regulators of the serine/threonine phosphatase 2A (PP2A) and the protein kinase A. Here, we characterize a Zds-like gene ZDS3 that plays a broad range of roles in the basidiomycetous pathogenic yeast Cryptococcus neoformans. ZDS3 harbors the conserved activation domain ZDS_C of Zds proteins. By gene disruption, ZDS3 is shown to play roles in capsule production, cell wall integrity, growth at a high temperature, resistance to H(2)O(2) stress, osmotic pressures and glucose-dependent invasive growth on the agar. As a consequence, the disruption of ZDS3 resulted in complete loss of virulence in a mouse cryptococcosis model. The data suggest that ZDS3 is a novel mediator of the virulence of C. neoformans. Zds3 may serve as an antifungal drug target as no homologs are found in mammals.