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

Abstract

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.

Figure 1. The spatial distribution of the different PQC compartments within a yeast cell

Model illustrating the different PQC compartments and their subcellular locations in yeast grown under normal growth conditions (top) or conditions of impaired protein quality control (bottom). Similar compartments have been described in mammalian cells, including the aggresome and ALIS (see text for details).

Figure 2. Pathways of spatial processing of misfolded proteins within the cell

Stress-denatured proteins interact with a number of sorting factors directing the misfolded proteins to individual PQC compartments within the cell, leading to refolding, degradation or terminal sequestration of the potentially toxic species.