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Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
10:27

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells

Published on: March 9, 2012

Ras1 acts through duplicated Cdc42 and Rac proteins to regulate morphogenesis and pathogenesis in the human fungal

Elizabeth Ripley Ballou1, Lukasz Kozubowski, Connie B Nichols

  • 1Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

Plos Genetics
|August 17, 2013
PubMed

Insights

Ras GTPases are crucial for fungal cell growth and virulence. In Cryptococcus neoformans, Ras1 regulates cell functions, with its defects impacting downstream Cdc42 and Rac GTPases essential for growth and pathogenesis.

Area of Science:

  • Cell Biology
  • Mycology
  • Molecular Genetics

Background:

  • Rho-type GTPases, including Ras, Cdc42, and Rac, are vital for eukaryotic cell proliferation and morphogenesis.
  • Cryptococcus neoformans, a fungus with paralogous Rho-GTPase genes, serves as a model to study their interactions.
  • RAS1 was previously identified as a key regulator of C. neoformans virulence, thermotolerance, and mating.

Purpose of the Study:

  • To investigate the roles of Ras GTPases and their downstream effectors in Cryptococcus neoformans.
  • To elucidate the specific functions of Cdc42 and Rac paralogs in fungal morphogenesis and pathogenesis.
  • To understand how redundant signaling pathways contribute to fungal survival under host-induced stress.

Main Methods:

  • Genetic analysis of ras1 deletion mutants (ras1Δ) in Cryptococcus neoformans.
  • Assessment of cellular defects including polarized growth, cytokinesis, and cell cycle progression.
  • Evaluation of the activity and roles of downstream Rho-GTPases (Cdc42, Cdc420, Rac1, Rac2).

Main Results:

  • Ras1 deletion mutants exhibited significant defects in thermotolerance, mating, polarized growth, cytokinesis, and cell cycle progression.
  • These ras1Δ defects were largely attributed to compromised activity of downstream Cdc42 and Rac paralogs.
  • Cdc42 paralogs were found to regulate septin localization and cytokinesis, while Rac paralogs primarily controlled polarized cell growth.

Conclusions:

  • Ras GTPases, particularly Ras1, are central regulators of C. neoformans morphogenesis and pathogenesis.
  • Distinct roles of Cdc42 and Rac paralogs, downstream of Ras1, highlight a robust signaling system for fungal adaptation.
  • The coordinated action of these duplicated GTPases enables Cryptococcus neoformans proliferation under host-derived cellular stresses.

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