Misfolded proteins impose a dosage-dependent fitness cost and trigger a cytosolic unfolded protein response in yeast

• DOI: 10.1073/pnas.1017570108
• Publication Date: 2010-12-28T01:45:14Z
• Authors: Kerry A. Geiler-S...; Michael F. Dion; Bogdan A. Budnik; Stephanie M. Wang; Daniel L. Hartl; D. Allan Drummond
• Keywords: Aggresome

Evolving lineages face a constant intracellular threat: most new coding sequence mutations destabilize the folding of encoded protein. Misfolded proteins form insoluble aggregates and are hypothesized to be intrinsically cytotoxic. Here, we experimentally isolate fitness cost caused by toxicity misfolded proteins. We exclude other costs protein misfolding, such as loss functional or attenuation growth-limiting synthesis resources, comparing growth rates budding yeast expressing folded variants gratuitous protein, YFP, at equal levels. quantify that increases with abundance, up much 3.2% rate reduction when YFP represents less than 0.1% total cellular Comparable experiments on gene orotidine-5′-phosphate decarboxylase ( URA3 ) produce similar results. Quantitative proteomic measurements reveal that, within cell, induces coordinated interacting cytosolic chaperone in absence wider stress response, providing evidence for an evolved modular response cytosol. These results underscore distinct evolutionarily relevant molecular threat independent function. Assuming impose costs, cells express almost all steady-state levels sufficient expose their encoding genes selection against lending credibility recent suggestion imposes global constraint evolution.