Comparative analysis of Cdc48-dependent proteolysis at the ER, mitochondria and chloroplasts

The ubiquitin-proteasome system (UPS) is the preeminent proteolytic system in eukaryotes. While soluble nucleocytosolic proteins are readily accessed by the UPS, organelle-localised proteins present major, membrane-related accessibility challenges. Cells overcome this problem by employing the conserved AAA+ ATPase Cdc48 to extract organellar proteins to the cytosol, thereby enabling proteasomal degradation. Major Cdc48-dependent proteolytic systems exist at the endoplasmic reticulum, mitochondria and chloroplasts, and are uniquely adapted to deliver protein homeostasis within the respective organelles. We provide a focused comparison of these systems, analysing similarities and differences between them. Better understanding of underlying principles has important implications spanning human health and agriculture.