Sorting out the trash: the spatial nature of eukaryotic protein quality control

•Spatial sequestration of misfolded proteins is an early, normal response to stress.•PQC compartments spatially restrict misfolded proteins thus enhancing degradation.•The ER acts as a dynamic network for the spatial distribution of misfolded proteins.•Spatial protein sequestration promotes rejuvenation of daughter cells in mitosis.•Altered PQC is associated with neurodegenerative disorders, cancer, and aging. Failure to maintain protein homeostasis is associated with aggregation and cell death, and underies a growing list of pathologies including neurodegenerative diseases, aging, and cancer. Misfolded proteins can be toxic and interfere with normal cellular functions, particularly during proteotoxic stress. Accordingly, molecular chaperones, the ubiquitin-proteasome system (UPS) and autophagy together promote refolding or clearance of misfolded proteins. Here we discuss emerging evidence that the pathways of protein quality control (PQC) are intimately linked to cell architecture, and sequester proteins into spatially and functionally distinct PQC compartments. This sequestration serves a number of functions, including enhancing the efficiency of quality control; clearing the cellular milieu of potentially toxic species and facilitating asymmetric inheritance of damaged proteins to promote rejuvenation of daughter cells.