A Limited Number of Amino Acid Permeases Are Crucial for Cryptococcus neoformans Survival and Virulence.

Abstract

One unique attribute of Cryptococcus neoformans is its ability to procure essential monomers from its surroundings to survive in diverse environments. Preferentially, sugars are the energy sources for this opportunistic pathogenic fungus under the carbon catabolite repression (CCR); however, sugar restriction induces alternative use of low molecular weight alcohol, organic acids, and amino acids. The expression of transmembrane amino acid permeases (Aaps) allows C. neoformans to utilize different amino acids and their conjugates, notwithstanding under the nitrogen catabolite repression (NCR). Being referred to as global permeases, there is a notion that all cryptococcal Aaps are important to survival and virulence. This functional divergence makes alternative drug targeting against Cryptococcus a challenge. We examine the functions and regulations of C. neoformans Aap variants with the aim of rationalizing their relevance to cryptococcal cell survival and virulence. Based on nutrient bioavailability, we linked the Cac1 pathway to Ras1 activation for thermotolerance that provides a temperature cushion for Aap activity under physiological conditions. Lastly, mutants of Aaps are examined for significant phenotypic deficiencies/advantages, which buttress the specific importance of limited numbers of Aaps involved in cryptococcal infections.