Pathogenic yeast uniquely resists toxicity of aggregation-prone proteins
Misfolded proteins can be so toxic that they cause cell death. At least nine neurodegenerative disorders are caused by misfolded proteins with expanded stretches of glutamine residues (polyQ tracts), including the invariably fatal Huntington’s disease. But some organisms are resistant to the harmful effects of these proteins. In the January issue of G3, Leach et al. report that the fungus Candida albicans, a common resident of the human body, can tolerate proteins with very long polyQ tracts—and the mechanism fueling this resistance seems unlike any known so far.
At first, the researchers were interested in polyQ proteins’ potential to cripple C. albicans because the yeast can cause disease—over 400,000 cases per year of which are life-threatening. But the researchers found that C. albicans is able to grow even when forced to produce large amounts of 230 Q-long proteins. Most other species studied so far, including the friendlier yeast Saccharomyces cerevisiae, can’t withstand such a flood of polyQs. Leach et al. had stumbled on a mystery: what makes these fungi so resistant to these normally toxic proteins?
Proteins with long polyQ stretches tend to form aggregates that have exposed hydrophobic surfaces, causing them to clump together with other proteins. That’s why they’re so harmful to the cell. But the researchers found that unlike Drosophila melanogaster, S. cerevisiae, and several other species, C. albicans showed no signs of protein aggregation in the cytosol or nucleus even when expressing massive quantities of polyQ proteins. And unlike in other species, polyQ protein expression in C. albicans didn’t lead to much of a change in transcription of other genes.
Notably, the heat shock response—which can normally be activated by misfolded proteins and helps mitigate their deleterious effects—was not affected by the buildup of polyQ proteins in C. albicans. Even knocking out the genes for various parts of the protein quality control machinery and inhibiting a major heat shock protein didn’t cause polyQ aggregation or toxicity. With the avenues of escape other organisms use to evade polyQ-induced damage unaffected, it’s not clear how C. albicans remains unscathed.
Even more mystifyingly, C. albicans does not have a large number of polyQ or other aggregation-prone proteins in its proteome; if it did, the yeast’s resistance would make sense in evolutionary terms. Further research on how this fungus avoids polyQ aggregation and toxicity will be of interest not only because these results are so perplexing but because learning the yeast’s secrets may lead to insight into how polyQ proteins in humans can lead to disease and even death.
Leach, M.; Kim, T.; DiGregorio, S.; Collins, C.; Zhang, Z.; Duennwald, M.; Cowen, L. Candida albicans Is Resistant to Polyglutamine Aggregation and Toxicity.
G3, 7(1), 95-108.