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Updated: May 25, 2026
Quantifying the Antifungal Activity of Peptides Against Candida albicans
Published on: January 13, 2023
Msb2 shedding protects Candida albicans against antimicrobial peptides
Eva Szafranski-Schneider1, Marc Swidergall, Fabien Cottier
1Department Biologie, Molekulare Mykologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
Abstract:
Msb2 is a sensor protein in the plasma membrane of fungi. In the human fungal pathogen C. albicans Msb2 signals via the Cek1 MAP kinase pathway to maintain cell wall integrity and allow filamentous growth. Msb2 doubly epitope-tagged in its large extracellular and small cytoplasmic domain was efficiently cleaved during liquid and surface growth and the extracellular domain was almost quantitatively released into the growth medium. Msb2 cleavage was independent of proteases Sap9, Sap10 and Kex2. Secreted Msb2 was highly O-glycosylated by protein mannosyltransferases including Pmt1 resulting in an apparent molecular mass of >400 kDa. Deletion analyses revealed that the transmembrane region is required for Msb2 function, while the large N-terminal and the small cytoplasmic region function to downregulate Msb2 signaling or, respectively, allow its induction by tunicamycin. Purified extracellular Msb2 domain protected fungal and bacterial cells effectively from antimicrobial peptides (AMPs) histatin-5 and LL-37. AMP inactivation was not due to degradation but depended on the quantity and length of the Msb2 glycofragment. C. albicans msb2 mutants were supersensitive to LL-37 but not histatin-5, suggesting that secreted rather than cell-associated Msb2 determines AMP protection. Thus, in addition to its sensor function Msb2 has a second activity because shedding of its glycofragment generates AMP quorum resistance.
Insights
Msb2 protein shedding in Candida albicans generates a glycofragment that protects fungal and bacterial cells from antimicrobial peptides, conferring quorum resistance. This dual function highlights Msb2
Area of Science:
- Mycology and Fungal Pathogenesis
- Cellular and Molecular Biology
- Host-Pathogen Interactions
Background:
- Msb2 is a plasma membrane sensor protein in fungi, crucial for cell wall integrity and filamentous growth in Candida albicans via the Cek1 MAP kinase pathway.
- Understanding Msb2's function and regulation is vital for developing strategies against fungal infections.
Purpose of the Study:
- To investigate the cleavage, secretion, and functional significance of the Msb2 protein in Candida albicans.
- To determine the role of secreted Msb2 glycofragments in antimicrobial peptide (AMP) resistance and fungal survival.
Main Methods:
- Epitope tagging of Msb2 to track its cleavage and localization.
- Protease activity assays to identify enzymes involved in Msb2 shedding.
- Biochemical analysis of secreted Msb2, including glycosylation and molecular mass determination.
- Functional assays using purified Msb2 extracellular domain to assess AMP inactivation.
- Genetic analysis of C. albicans msb2 mutants for sensitivity to AMPs.
Main Results:
- Msb2 undergoes efficient cleavage, releasing its large extracellular domain into the growth medium, independent of Sap9, Sap10, and Kex2 proteases.
- Secreted Msb2 is heavily O-glycosylated, reaching >400 kDa, and its extracellular domain effectively inactivates antimicrobial peptides like histatin-5 and LL-37.
- Candida albicans msb2 mutants exhibit hypersensitivity to LL-37, indicating that secreted Msb2 is key for AMP protection and confers quorum resistance.
Conclusions:
- Msb2 possesses a dual function: sensing environmental cues and generating a secreted glycofragment that provides antimicrobial peptide resistance.
- The shedding of Msb2's glycofragment is a novel mechanism for establishing antimicrobial peptide quorum resistance in Candida albicans.
- These findings offer new insights into fungal virulence mechanisms and potential therapeutic targets.
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