Misfolded proteins in yeast and mammalian cells are sequestered in two distinct quality control compartments: the juxtanuclear inclusion (JUNQ) and the perivacuolar inclusion (IPOD). The partitioning of misfolded proteins depends on their ubiquitination status and aggregation state. Soluble ubiquitinated misfolded proteins accumulate in the JUNQ, where proteasomes are concentrated, while terminally aggregated proteins are sequestered in the IPOD. Disease-associated proteins like Huntington and prion proteins are preferentially directed to the IPOD. Enhancing ubiquitination of prion proteins promotes their delivery to the JUNQ. These compartments may represent two cellular strategies for sequestering aggregation-prone, potentially toxic polypeptides. The JUNQ is more prevalent under normal conditions and is involved in the degradation and refolding of misfolded proteins, while the IPOD is associated with insoluble aggregates and may facilitate their clearance through autophagy. The JUNQ and IPOD are distinct subcellular compartments with different solubility states and diffusion properties. The JUNQ contains soluble misfolded proteins, while the IPOD contains non-diffusing, possibly insoluble species. Ubiquitination plays a key role in determining the partitioning of misfolded proteins between these compartments. Amyloidogenic proteins are preferentially targeted to the IPOD, suggesting it is the preferred cellular destination for protein aggregates. The findings provide a framework for understanding the preferential accumulation of amyloidogenic proteins in inclusions linked to human disease.Misfolded proteins in yeast and mammalian cells are sequestered in two distinct quality control compartments: the juxtanuclear inclusion (JUNQ) and the perivacuolar inclusion (IPOD). The partitioning of misfolded proteins depends on their ubiquitination status and aggregation state. Soluble ubiquitinated misfolded proteins accumulate in the JUNQ, where proteasomes are concentrated, while terminally aggregated proteins are sequestered in the IPOD. Disease-associated proteins like Huntington and prion proteins are preferentially directed to the IPOD. Enhancing ubiquitination of prion proteins promotes their delivery to the JUNQ. These compartments may represent two cellular strategies for sequestering aggregation-prone, potentially toxic polypeptides. The JUNQ is more prevalent under normal conditions and is involved in the degradation and refolding of misfolded proteins, while the IPOD is associated with insoluble aggregates and may facilitate their clearance through autophagy. The JUNQ and IPOD are distinct subcellular compartments with different solubility states and diffusion properties. The JUNQ contains soluble misfolded proteins, while the IPOD contains non-diffusing, possibly insoluble species. Ubiquitination plays a key role in determining the partitioning of misfolded proteins between these compartments. Amyloidogenic proteins are preferentially targeted to the IPOD, suggesting it is the preferred cellular destination for protein aggregates. The findings provide a framework for understanding the preferential accumulation of amyloidogenic proteins in inclusions linked to human disease.