A Putative P-Type ATPase, Apt1, Is Involved in Stress Tolerance and Virulence in Cryptococcus neoformans
- 1 January 2010
- journal article
- Published by American Society for Microbiology in Eukaryotic Cell
- Vol. 9 (1), 74-83
- https://doi.org/10.1128/ec.00289-09
Abstract
The export of virulence factors, such as the capsule polysaccharide, to the cell surface is a critical aspect of the pathogenicity of Cryptococcus neoformans. A view of capsule export via exocytosis and extracellular vesicles is emerging, but the molecular mechanisms underlying virulence factor transport pathways remain to be established. In this study, we characterized the APT1 gene, which encodes a predicted integral membrane P-type ATPase belonging to the type IV, Drs2 family of aminophospholipid translocases (flippases) (APTs). APTs maintain the phospholipid asymmetry that is critical in membrane fusion events for trafficking and in establishing cell polarity. Deletion of the APT1 gene resulted in phenotypes consistent with similar roles in C. neoformans . These included altered actin distribution, increased sensitivity to stress conditions (oxidative and nitrosative stress) and to trafficking inhibitors, such as brefeldin A and monensin, a reduction in exported acid phosphatase activity, and hypersensitivity to the antifungal drugs amphotericin B, fluconazole, and cinnamycin. However, there was no difference in growth, capsule size, or melanin production between the wild type and the apt1 mutant strains at either 30°C or 37°C. Despite the absence of an influence on these major virulence factors, Apt1 was required for survival during interactions with macrophages, and apt1 mutants exhibited attenuated virulence in a mouse inhalation model of cryptococcosis. Therefore, Apt1 contributes to virulence and the stress response in C. neoformans through apparent functions in membrane fusion and trafficking that do not influence the deposition of major virulence factors, such as capsule and melanin, outside the cell.Keywords
This publication has 64 references indexed in Scilit:
- Role of Ferroxidases in Iron Uptake and Virulence of Cryptococcus neoformansEukaryotic Cell, 2009
- Identification of ENA1 as a Virulence Gene of the Human Pathogenic Fungus Cryptococcus neoformans through Signature-Tagged Insertional MutagenesisEukaryotic Cell, 2009
- The Cryptococcus neoformans Rho-GDP Dissociation Inhibitor Mediates Intracellular Survival and VirulenceInfection and Immunity, 2008
- Metabolic adaptation in Cryptococcus neoformans during early murine pulmonary infectionMolecular Microbiology, 2008
- P4-ATPase Requirement for AP-1/Clathrin Function in Protein Transport from the trans-Golgi Network and Early EndosomesMolecular Biology of the Cell, 2008
- JCI Insight, 2008
- Extracellular Vesicles Produced by Cryptococcus neoformans Contain Protein Components Associated with VirulenceEukaryotic Cell, 2008
- Eca1, a Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase, Is Involved in Stress Tolerance and Virulence inCryptococcus neoformansInfection and Immunity, 2007
- Vesicular Polysaccharide Export in Cryptococcus neoformans Is a Eukaryotic Solution to the Problem of Fungal Trans-Cell Wall TransportEukaryotic Cell, 2007
- A Eukaryotic Capsular Polysaccharide Is Synthesized Intracellularly and Secreted via ExocytosisMolecular Biology of the Cell, 2006