ER Quality Control: The Cytoplasmic Connection

unfolded substrate into the active site. Proteasomes The endoplasmic reticulum (ER) is the port of entry of are abundant in the cytoplasm and nucleus, but are membrane and secretory proteins into the central vacuapparently absent from the ER lumen. olar system, which includes the ER itself, the Golgi appaMutations in the cystic fibrosis transmembrane conratus, lysosomes, endosomes, the plasma membrane, ductance regulator (CFTR), a polytopic integral memand intermediate transport compartments. The ER is brane protein, cause the human genetic disease cystic also the site where nascent secretory and membrane fibrosis by interfering with the biosynthetic folding of proteins acquire their mature tertiary and quaternary nascent CFTR polypeptides in the ER and targeting them structures. “Quality control” mechanisms in the ER enfor rapid destruction via a process bearing all of the sure that nascent proteins that fail to fold or to oligohallmarks of classical “ER degradation” (reviewed by merize correctly are not deployed to distal compartWard and Kopito, 1996). Evidence of a role for the proments of the secretory pathway and, following a lag teasome inCFTR degradation, suggested by its sensitivperiod of variable duration, are rapidly degraded (reity to inhibition by lactacystin, was strengthened by the viewed by Hammond and Helenius, 1995) (Figure 1). discovery that undegraded CFTR molecules that accuBecause this process is independent of lysosomal funcmulate in the presence of lactacystin are modified by tion and because degradation substrates can be localcovalently attached multiubiquitin chains (Ward et al., ized to the ER region by immunocytochemistry, it has 1995). Moreover, mutant CFTR molecules are stabilized been generally assumed that the degradation occurs by coexpression of UbK48R, a dominant negative form within the ER itself and it has been termed “ER degradaof ubiquitin that is unable to form multiubiquitin chains, tion” (reviewed by Klausner and Sitia, 1990). However, and by conditional inactivation of the ubiquitin-activatthe abundance in the ER lumen of unfolded and partially ing enzyme, E1 (Ward et al., 1995). folded polypeptide chains that are highly susceptible to Additional evidence supporting a role for the ubiquitin proteolysis is difficult to reconcile with the presence pathway in ER degradation was suggested by the gein the same compartment of an aggressive proteolytic netic interaction between UBC6, a ubiquitin-conjugating apparatus. Is there a proteolytic subcompartment within enzyme that is associated with the cytoplasmic face of the ER into which misfolded substrates are segregated? the ER membrane and SEC61, which encodes an ERHow does this system distinguish proteins that are in resident polytopic integral membrane protein (Sommer the process of folding from those that are unable to and Jentsch, 1993). Mutant, unassembled forms of fold? How can this system degrade integral membrane Sec61p are rapidly degraded by a process requiring proteins which are exposed to three different compart-