ER Quality Control: The Cytoplasmic Connection

Abstract

The endoplasmic reticulum (ER) is the port of entry of membrane and secretory proteins into the central vacuolar system, which includes the ER itself, the Golgi apparatus, lysosomes, endosomes, the plasma membrane, and intermediate transport compartments. The ER is also the site where nascent secretory and membrane proteins acquire their mature tertiary and quaternary structures. “Quality control” mechanisms in the ER ensure that nascent proteins that fail to fold or to oligomerize correctly are not deployed to distal compartments of the secretory pathway and, following a lag period of variable duration, are rapidly degraded (reviewed byHammond and Helenius 1995) (Figure 1). Because this process is independent of lysosomal function and because degradation substrates can be localized to the ER region by immunocytochemistry, it has been generally assumed that the degradation occurs within the ER itself and it has been termed “ER degradation” (reviewed byKlausner and Sitia 1990). However, the abundance in the ER lumen of unfolded and partially folded polypeptide chains that are highly susceptible to proteolysis is difficult to reconcile with the presence in the same compartment of an aggressive proteolytic apparatus. Is there a proteolytic subcompartment within the ER into which misfolded substrates are segregated? How does this system distinguish proteins that are in the process of folding from those that are unable to fold? How can this system degrade integral membrane proteins which are exposed to three different compartments (lumen, cytoplasm, and membrane)?