The calcium transporter Pmc1 provides Ca2+ tolerance and influences the progression of murine cryptococcal infection

• Published in: The FEBS journal 2013-10, Vol.280 (19), p.4853-4864
• Main Authors: Kmetzsch, Livia, Staats, Charley C., Cupertino, Julia B., Fonseca, Fernanda L., Rodrigues, Marcio L., Schrank, Augusto, Vainstein, Marilene H.
• Format: Article
• Language: English
• Subjects: Animals; Calcium; Calcium - metabolism; calcium transport; Calcium-Transporting ATPases - classification; Calcium-Transporting ATPases - genetics; Calcium-Transporting ATPases - metabolism; cryptococcosis; Cryptococcosis - metabolism; Cryptococcus neoformans; Cryptococcus neoformans - enzymology; Cryptococcus neoformans - genetics; Cryptococcus neoformans - pathogenicity; Cryptococcus neoformans; Fungal Proteins - classification; Fungal Proteins - genetics; Fungal Proteins - metabolism; Fungi; Infections; Mice; Pathogenesis; Phylogeny; vacuolar calcium storage; Vacuoles - enzymology; Virulence
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.12458

The Ca2+‐calcineurin signaling pathway in the human fungal pathogen Cryptococcus neoformans is essential for adaptation to the host environment during infection. Calcium transporters regulate cytosolic calcium concentrations, providing Ca2+ loading into storage organelles. The three calcium transporters that have been characterized in C. neoformans, Cch1, Eca1 and Vcx1, are required for fungal virulence, supporting a role for calcium‐mediated signaling in cryptococcal pathogenesis. In the present study, we report the functional characterization of the putative vacuolar calcium ATPase Pmc1 in C. neoformans. Our results demonstrate that Pmc1 provides tolerance to high Ca2+ concentrations. The double knockout of C. neoformans PMC1 and VCX1 genes impaired the intracellular calcium transport, resulting in a significant increase in cytosolic calcium levels. Furthermore, Pmc1 was essential for both the progression of pulmonary infection and brain colonization in mice, emphasizing the crucial role of calcium signaling and transport for cryptococcal pathogenesis. The three calcium transporters characterized in Cryptococcus neoformans, Cch1, Eca1, and Vcx1 are required for virulence. We reported the characterization of the putative vacuolar calcium ATPase Pmc1. Disruption of PMC1 led to impaired capsule formation under specific conditions. Pmc1 was essential for the progression of pulmonary infection in mice, emphasizing the crucial role of calcium transport for cryptococcal pathogenesis.