Two CDC42 paralogues modulate Cryptococcus neoformans thermotolerance and morphogenesis under host physiological...

Area of Science:

• Mycology
• Cell Biology
• Pathogenesis

Background:

• Morphogenesis regulation is vital for cellular stress response, particularly against microbial pathogens.
• The polarity protein Cdc42 is a key regulator of morphogenesis across eukaryotes.
• Cryptococcus neoformans, a human fungal pathogen, uniquely possesses two Cdc42 paralogues: Cdc42 and Cdc420.

Purpose of the Study:

• To investigate the distinct roles of Cdc42 and Cdc420 in Cryptococcus neoformans.
• To determine the contribution of each Cdc42 paralogue to host stress resistance and virulence.
• To elucidate the regulatory pathways involving Cdc42 paralogues in fungal morphogenesis.

Main Methods:

• Comparative analysis of Cdc42 and Cdc420 function under various stress conditions.
• Assessment of actin and septin organization in relation to Cdc42 paralogues.
• Investigation of the downstream effects of Cdc42 paralogues on morphogenesis and mating pathways.
• Evaluation of Cdc42 upregulation in response to temperature stress.
• Assessment of fungal virulence in a murine model of cryptococcosis.

Main Results:

• Cdc42 and Cdc420 are not essential for viability under non-stress conditions but are required for high-temperature resistance.
• The paralogues exhibit differential roles in actin and septin organization.
• Cdc42 and Cdc420 function downstream of Ras1 in the morphogenesis sub-pathway, but not in mating.
• Cdc42 is upregulated during temperature stress and is essential for virulence.
• Cdc420 does not show significant upregulation or a requirement for virulence.

Conclusions:

• Cdc42 and Cdc420 play distinct, complementary roles in Cryptococcus neoformans morphogenesis and stress response.
• Cdc42 is a critical virulence factor, particularly under temperature stress.
• These Cdc42 paralogues likely collaborate with other Rho-like GTPases to control cell polarity and survival.