Amino Acid Sensing and Assimilation by the Fungal Pathogen Candida albicans in the Human Host

Abstract

Nutrient uptake is essential for cellular life and the capacity to perceive extracellular nutrients is critical for coordinating their uptake and metabolism. Commensal fungal pathogens, e.g., Candida albicans, have evolved in close association with human hosts and are well-adapted to using diverse nutrients found in discrete host niches. Human cells that cannot synthesize all amino acids require the uptake of the “essential amino acids” to remain viable. Consistently, high levels of amino acids circulate in the blood. Host proteins are rich sources of amino acids but their use depends on proteases to cleave them into smaller peptides and free amino acids. C. albicans responds to extracellular amino acids by pleiotropically enhancing their uptake and derive energy from their catabolism to power opportunistic virulent growth. Studies using Saccharomyces cerevisiae have established paradigms to understand metabolic processes in C. albicans; however, fundamental differences exist. The advent of CRISPR/Cas9-based methods facilitate genetic analysis in C. albicans, and state-of-the-art molecular biological techniques are being applied to directly examine growth requirements in vivo and in situ in infected hosts. The combination of divergent approaches can illuminate the biological roles of individual cellular components. Here we discuss recent findings regarding nutrient sensing with a focus on amino acid uptake and metabolism, processes that underlie the virulence of C. albicans.

Proline catabolism is key to facilitatingCandida albicanspathogenicity

“…2D). In the absence of glucose, we found that the expression of cytoplasmic Gdh2 (8) , one of the key enzymes in central nitrogen metabolism, is partly regulated by Put3 (Fig. 2D).…”

“…In C. albicans , as in S. cerevisiae , proline catabolism is induced by the presence of proline and due to being mitochondrial localized is sensitive to glucose repression (reviewed in ( 8 )) (Fig. 2A).…”

“…The growth-inhibitory effects of proline are dependent on non-fermentative conditions when mitochondrial respiration is required. The lack of proline inhibition of cells grown in high glucose media is due to glucose repression of mitochondrial activity (10) (reviewed in (8) ). Consistent with this notion, Put1 and Put2 protein levels are elevated in wildtype cells 1 h after the addition of 10 mM proline in SGL and to a lesser extent in SD (Fig.…”

“…1). Accumulating evidence indicates that key regulatory differences exist between C. albicans and S. cerevisiae , which likely reflect the microenvironments in which they evolved (reviewed in (8) ). S. cerevisiae evolved for life in high sugar environments and is widely found in nature.…”

“…In some pathological states, such as cancer and sarcopenia, proline is released in significant quantities as a result of ECM degradation by extracellular proteases (6,7), generating a proline pool that can be assimilated by human cells and the associated microbiome. In eukaryotes, proline catabolism occurs largely in mitochondria, and its complete oxidation can generate ~30 equivalents of ATP, making proline an excellent energy source (3,8,9). Candida spp.…”