Abstract
Proliferation and morphogenesis in eukaryotic cells depend on the concerted activity of Rho-type GTPases, including Ras, Cdc42, and Rac. The sexually dimorphic fungus Cryptococcus neoformans, which encodes paralogous, non-essential copies of all three, provides a unique model in which to examine the interactions of these conserved proteins. Previously, we demonstrated that RAS1 mediates C. neoformans virulence by acting as a central regulator of both thermotolerance and mating. We report here that ras1Δ mutants accumulate defects in polarized growth, cytokinesis, and cell cycle progression. We demonstrate that the ras1Δ defects in thermotolerance and mating can be largely explained by the compromised activity of four downstream Rho-GTPases: the Cdc42 paralogs, Cdc42 and Cdc420; and the Rac paralogs, Rac1 and Rac2. Further, we demonstrate that the separate GTPase classes play distinct Ras-dependent roles in C. neoformans morphogenesis and pathogenesis. Cdc42 paralogs primarily control septin localization and cytokinesis, while Rac paralogs play a primary role in polarized cell growth. Together, these duplicate, related signaling proteins provide a robust system to allow microbial proliferation in the presence of host-derived cell stresses.
Highlights
Ras GTPases are central regulators of cell proliferation in all eukaryotes, and perturbations that impair Ras signal transduction have profound effects on cellular morphogenesis and function
We demonstrate that the ras1D defects in thermotolerance can be largely explained by disordered Cdc42 and septin protein function, while hyphal morphogenesis, cell polarity, and cell cycle regulation are primarily mediated by Rac GTPases
Previous work from our group suggests that the CnRac proteins are primarily involved in cell polarization events, while the CnCdc42 proteins are more specialized to direct cytokinesis and septin localization
Summary
Ras GTPases are central regulators of cell proliferation in all eukaryotes, and perturbations that impair Ras signal transduction have profound effects on cellular morphogenesis and function. In mammalian cells, activating mutations of RAS genes result in malignant transformation via multiple anti-apoptotic and proliferative pathways [1]. Activating Ras mutations in fungi lead to altered morphogenesis and increased substrate invasion [2,3,4,5]. In each instance, these Ras mutations stimulate proliferation and invasion through the aberrant regulation of multiple downstream effectors. Proliferation is repressed by the loss of Ras function. Cryptococcus neoformans ras1D mutants exhibit defects in polarized growth and cell cycle progression, arresting as large, round cells upon exposure to temperature stress [2]
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