Misfolded proteins can undergo different fates. Obviously, refolding is the best way to go. However, if a protein is intrinsically misfolded it can be targeted for degradation by the proteasome. If the ubiquitin-proteasome system is malfunctioning or otherwise overwhelmed, misfolded proteins can be sequestered into inclusion bodies. Clearly, there is a quality control stage in which the fate of the protein must be decided: to fold, to aggregate, or to be eliminated. How precisely this triage decision is made is currently unknown and we address this question using model substrate in yeast cells.

Genetic studies in our laboratory indicate that the yeast Hsp70 chaperone Ssa1 and the Hsp40 chaperone sis1 are essential for the degradation of a model misfolded substrate harboring a protein quality control degrons (Furth et al., 2011; Shiber et al., 2013). However, these chaperones play different roles in substrate proteolysis. Whereas the Hsp40 Sis1 is absolutely required for ubiquitin conjugation, the Hsp70 Ssa1 is not. Our finding localizes Sis1 function to the early stage of substrate targeting the ubiquitin system while Ssa1 likely functions downstream to the ubiquitin system, probably by escorting the ubiquitylated substrate to the proteasome.

In the absence of Hsp70 chaperones misfolded substrates can form cytosolic aggregates similar to those that appear in misfolded protein diseases (also called neurodegenerative diseases), such as Alzheimer’s, Huntington’s, and Parkinson’s that are harmful to the cell (see the movie). Understanding the mechanism of ubiquitin-mediated aggregate formation in yeast may provide important information about the role of ubiquitin in the aggregates associated with neurodegenerative diseases (Shiber and Ravid, 2014).