Characterization of endoplasmic reticulum-associated degradation in the human fungal pathogen Candida albicans

Author:

Doss Ellen M.12ORCID,Moore Joshua M.1,Harman Bryce H.1,Doud Emma H.34,Rubenstein Eric M.1ORCID,Bernstein Douglas A.1

Affiliation:

1. Department of Biology, Ball State University, Muncie, Indiana, United States

2. Mode of Action and Resistance Management Center of Expertise, Corteva Agriscience, Indianapolis, Indiana, United States

3. Center for Proteome Analysis, Indiana University School of Medicine, Indianapolis, Indiana, United States

4. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States

Abstract

Background Candida 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 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). Methods Here we perform the first characterization, to our knowledge, of ERAD in a human fungal pathogen. We generated functional knockouts of C. albicans genes encoding three proteins predicted to play roles in ERAD, the ubiquitin ligases Hrd1 and Doa10 and the ubiquitin-conjugating enzyme Ubc7. We assessed the fitness of each mutant in the presence of proteotoxic stress, and we used quantitative tandem mass tag mass spectrometry to characterize proteomic alterations in yeast lacking each gene. Results Consistent with a role in protein quality control, yeast lacking proteins thought to contribute to ERAD displayed hypersensitivity to proteotoxic stress. Furthermore, each mutant displayed distinct proteomic profiles, revealing potential physiological ERAD substrates, co-factors, and compensatory stress response factors. Among candidate ERAD substrates are enzymes contributing to ergosterol synthesis, a known therapeutic vulnerability of C. albicans. Together, our results provide the first description of ERAD function in C. albicans, and, to our knowledge, any pathogenic fungus.

Publisher

PeerJ

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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