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Published on: September 21, 2021
Candida albicans Is Resistant to Polyglutamine Aggregation and Toxicity
Michelle D Leach1,2, TaeHyung Kim3,4, Sonja E DiGregorio5
1Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, AB25 2ZD, UK.
Abstract:
Disruption of protein quality control can be detrimental, having toxic effects on single cell organisms and contributing to neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's in humans. Here, we examined the effects of polyglutamine (polyQ) aggregation in a major fungal pathogen of humans, Candida albicans, with the goal of identifying new approaches to disable this fungus. However, we discovered that expression of polyQ stretches up to 230Q had no effect on C. albicans ability to grow and withstand proteotoxic stress. Bioinformatics analysis demonstrates that C. albicans has a similarly glutamine-rich proteome to the unicellular fungus Saccharomyces cerevisiae, which exhibits polyQ toxicity with as few as 72Q. Surprisingly, global transcriptional profiles indicated no significant change upon induction of up to 230Q. Proteomic analysis highlighted two key interactors of 230Q, Sis1 and Sgt2; however, loss of either protein had no additional effect on C. albicans toxicity. Our data suggest that C. albicans has evolved powerful mechanisms to overcome the toxicity associated with aggregation-prone proteins, providing a unique model for studying polyQ-associated diseases.
Insights
Candida albicans resists toxic protein aggregation, unlike other fungi. This fungus has evolved strong defenses against polyglutamine (polyQ) toxicity, offering insights into neurodegenerative diseases.
Area of Science:
- Microbiology
- Molecular Biology
- Biochemistry
Background:
- Protein quality control is vital, as its disruption causes cellular toxicity and contributes to human neurodegenerative diseases like Alzheimer's.
- Polyglutamine (polyQ) aggregation is a key factor in several neurodegenerative conditions.
- Candida albicans is a significant human fungal pathogen.
Purpose of the Study:
- To investigate the effects of polyglutamine (polyQ) aggregation in Candida albicans.
- To explore potential new strategies for disabling this fungal pathogen by understanding its response to proteotoxic stress.
- To compare polyQ toxicity in C. albicans with other organisms, particularly Saccharomyces cerevisiae.
Main Methods:
- Expression of polyglutamine (polyQ) stretches of varying lengths in C. albicans.
- Bioinformatics analysis of the C. albicans proteome for glutamine-rich proteins.
- Global transcriptional profiling to assess gene expression changes.
- Proteomic analysis to identify protein interactors of polyQ expansions.
- Gene deletion studies to examine the role of key interactors (Sis1 and Sgt2).
Main Results:
- C. albicans tolerates polyglutamine (polyQ) expansions up to 230Q without impaired growth or increased susceptibility to proteotoxic stress.
- Bioinformatics revealed a glutamine-rich proteome in C. albicans, yet it lacks the toxicity observed in Saccharomyces cerevisiae with shorter polyQ repeats (72Q).
- Transcriptional profiling showed no significant changes upon induction of polyQ expansions.
- Proteomic analysis identified Sis1 and Sgt2 as interactors of 230Q, but their absence did not exacerbate toxicity.
Conclusions:
- Candida albicans possesses robust mechanisms to counteract the toxicity of aggregation-prone proteins, specifically polyglutamine (polyQ) expansions.
- The fungus serves as a unique model system for studying the protective strategies against polyQ-associated diseases.
- Understanding these mechanisms could offer novel therapeutic targets for fungal infections and insights into neurodegenerative disease resilience.
