Misfolded proteins partition between two distinct quality control compartments

The accumulation of misfolded proteins in intracellular amyloid inclusions, typical of many neurodegenerative disorders including Huntington’s and prion disease, is thought to occur after failure of the cellular protein quality control mechanisms. Here we examine the formation of misfolded protein inclusions in the eukaryotic cytosol of yeast and mammalian cell culture models. We identify two intracellular compartments for the sequestration of misfolded cytosolic proteins. Partition of quality control substrates to either compartment seems to depend on their ubiquitination status and aggregation state. Soluble ubiquitinated misfolded proteins accumulate in a juxtanuclear compartment where proteasomes are concentrated. In contrast, terminally aggregated proteins are sequestered in a perivacuolar inclusion. Notably, disease-associated Huntingtin and prion proteins are preferentially directed to the perivacuolar compartment. Enhancing ubiquitination of a prion protein suffices to promote its delivery to the juxtanuclear inclusion. Our findings provide a framework for understanding the preferential accumulation of amyloidogenic proteins in inclusions linked to human disease. Despite the sophistication of the molecular chaperone system that catalyses the folding of polypeptides into their final native state, protein misfolding can occur. The wellbeing of the cell depends on how it manages the 'rejects'. Kaganovich et al. demonstrate that yeast and mammalian cells contain a cellular quality control pathway that distinguishes between soluble and insolubly aggregated proteins, and directs them to one of two inclusions. Soluble misfolded proteins that can be degraded by the proteasome or refolded are targeted to a juxtanuclear quality control compartment, and insoluble aggregates including disease-associated huntingtin and prion proteins are sequestered in a cytosolic inclusion associated with the autophagic pathway.