Quality Control of Protein Folding in the Cytosol

In order to function properly, newly synthesised proteins must rapidly and efficiently attain their native conformations. If they fail to do so, the cell may be adversely affected due to loss of function or toxic gain of function effects of misfolded polypeptides. Effective quality control mechanisms to recognise and eliminate misfolded proteins are thus critical for cell viability. The primary means by which misfolded proteins are selectively removed from the cell is via the ubiquitin–proteasome system. Although much is known about regulated proteolysis, how any given protein, which could potentially misfold, is recognised and targeted for proteasomemediated degradation has been challenging to decipher. Recent progress, much of it in yeast, has identified specific E3 ligases involved in this process, clarified or added to our knowledge of the roles of molecular chaperones, and identified multiple cellular locations where degradation, or failing that, aggregation, occurs.