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Stimuli that induce production of Candida albicans extracellular aspartyl proteinase

Abbott Laboratories, Anti-infective Research Division of Pharmaceutical Discovery, D47M-AP9A, 1 Abbott Park Road, Abbott Park, IL 60064-3500, USA

^* Author for correspondence. Tel. (708) 937 4477; fax (708) 938 6603; e-mail: goldmanr@randb.abbott.com.

ABSTRACT

Summary: Several species of the opportunistic fungal pathogen Candida produce an extracellular aspartyl proteinase that may assist the organism to invade and colonize host tissues, evade the host immune response and assimilate nitrogen from proteinaceous sources. Although addition of exogenous proteins, such as bovine serum albumin (BSA), to cultures of C. albicans is known to elicit proteinase production, the precise molecular mechanisms controlling regulation of proteinase induction are unknown. We have examined the ability of a variety of macromolecules to induce proteinase production using a chemically-defined nitrogen-limited growth medium and a rapid, sensitive microtitre fluorescent assay for proteinase activity in culture supernatants. BSA and the extracellular matrix protein collagen induced proteinase production. Homopolymers of both poly-L- and poly-D-glutamate also induced proteinase activity, whereas polyglycine, heparin sulphate and dextran sulphate did not. Thus, molecular recognition of proteinase-inducing stimuli is not highly stereospecific, but apparently requires both main- and side-chain interactions. Peptides 8 or more residues in length generally induced proteinase production while most shorter peptides did not. These data reveal that internalization of small peptides with less than 7 residues by peptide transport was not the inducing signal for proteinase production, since Candida dipeptide and oligopeptide permeases do not efficiently transport peptides of more than 6-7 residues. In addition a tight-binding synthetic inhibitor of Candida proteinase (K_i = 0.17 nM) prevented growth of C. albicans on BSA as a sole nitrogen source by blocking protein degradation. Immunodetection of proteinase in these culture supernatants suggests that fully intact proteins, in addition to peptide fragments of sufficient size, are capable of inducing proteinase production. A model involving stimulation of a plasma membrane signal transduction event by extracellular protein and/or polypeptide ligands of more than seven residues is compatible with these data.

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