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Characterization of Endoplasmic Reticulum-Associated Degradation in the human fungal pathogen C. albicans

ABSTRACT: C. albicans is the most prevalent human fungal pathogen. In immunocompromised individuals, C. albicans can cause serious systemic disease and patients infected with drug-resistant isolates have few treatment options. The Ubiquitin-Proteasome System has not been thoroughly characterized in C. albicans. Research from other model organisms has shown ubiquitination is important for protein quality control and regulated protein degradation at the endoplasmic reticulum (ER) via ER-associated protein degradation (ERAD). Here we perform the first characterization of ERAD in a human fungal pathogen. We generated functional knockouts of three proteins predicted to play roles in ERAD. Consistent with a role in protein quality control, yeast lacking proteins thought to play a role in ERAD displayed hypersensitivity to proteotoxic stress. Furthermore, each mutant displayed distinct proteomic profiles, revealing potential candidate physiological ERAD substrates, co-factors, and compensatory stress response factors. Together, our results provide the first description of ERAD function in C. albicans, and, to our knowledge, any pathogenic fungus.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Candida Albicans (ncbitaxon:5476)

SUBMITTER: Amber L. Mosley Douglas Bernstein

PROVIDER: MSV000091843 | MassIVE | Wed May 03 08:27:00 BST 2023

SECONDARY ACCESSION(S): PXD041949

REPOSITORIES: MassIVE

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Project description:Transcriptional profiling of CDC53 down-regulated Candida albicans cells compared to control cells Keywords: comparative genomic hybridization, genetic modification Candida albicans is an important opportunistic human fungal pathogen, which can cause mucosal as well as systemic infections in immunocompromised patients. Critical for the virulence of C. albicans is its ability to undergo a morphological transition from yeast to hyphal growth mode. Proper induction of filamentation is dependent on the ubiquitination pathway, which targets proteins for proteasome-mediated protein degradation or activates them for signaling events. In the present study, we evaluated the role of ubiquitination in C. albicans by impairing the function of the major ubiquitin-ligase complex SCF. This was done by depleting its backbone, the cullin Cdc53p (orf19.1674), using a tetracycline down-regulatable promoter system. Cdc53p-depleted cells displayed an invasive phenotype and constitutive filamentation under conditions favouring yeast growth mode, both on solid and in liquid media. In addition, these cells exhibited an early onset of cell death, as judged from propidium iodide staining, suggesting that CDC53 is an essential gene in C. albicans. To identify Cdc53p-dependent pathways in C. albicans, a genome-wide expression analysis was carried out that revealed a total of 425 differentially expressed genes (fold change â¥ 2, p-value â¤ 0.05) with 192 up- and 233 down-regulated genes in the CDC53-repressed mutant as compared to the control strain. GO term analysis identified biological processes significantly affected by Cdc53p depletion, including amino acid starvation response, with 14 genes being targets of the transcriptional regulator Gcn4p, and reductive iron transport. These results indicate that Cdc53p enables C. albicans to adequately respond to environmental signals. Two-strain experiment, CDC53-repressible cells vs. control cells, both grown in the presence of 20 Âµg/ml Doxycycline. Four independent biological replicates of total RNA of each strain, dye-swap.

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Characterization of Endoplasmic Reticulum-Associated Degradation in the human fungal pathogen C. albicans

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