Cellular biosynthesis of polypeptides generates misfolded proteins as a result of off-pathway folding events. Genetic and environmental stress trigger protein misfolding and challenges the functional integrity of the entire proteome.

The primary line of defense against the accumulation of misfolded polypeptides is protein quality control (PQC). PQC mechanisms rely on molecular chaperones of the Heat-shock protein 70 kDa (Hsp70) class. Hsp70 binds to exposed hydrophobic segments of non-natively folded polypeptides and promote their solubility and continued folding in a dynamic ATP-consuming process. Substrates that interact with Hsp70 but that do not reach native conformations are targeted for proteolytic degradation by the ubiquitin-proteasome system. At present, the mechanisms of PQC are poorly understood and it is not known what factors determine the fate of polypeptides in folding and degradation.

We employ genetic, cell biological and biochemical approaches in the study of the cytosolic Hsp70 machinery in budding yeast to elucidate the factors and mechanisms of PQC. Specifically, we focus on the role of Hsp70 nucleotide exchange factors (NEFs) in protein triage decisions of PQC. In this project we investigate fundamental biological mechanisms that are of central importance for the understanding of how cells respond and adapt to proteotoxic stress conditions.