Cooh-Terminal Truncations Promote Proteasome-Dependent Degradation of Mature Cystic Fibrosis Transmembrane Conductance Regulator from Post-Golgi Compartments

Benharouga, Mohamed; Haardt, Martin; Kartner, Norbert; Lukacs, Gergely L.

Newly synthesized secretory and membrane proteins must attain their native conformation spontaneously or with the assistance of ER-resident and cytosolic chaperones before their export from the ER. The ER quality control mechanism assures that functionally incompetent, misfolded, or unassembled oligomeric proteins are retained and targeted for proteolysis via the ER-associated degradation (ERAD) 1 pathway (Hurtley and Helnius, 1989; Brodsky and McCracken, 1997; Bonifacino and Weismann, 1998; Ellgaard et al., 1999; Wickner et al., 1999) . The ERAD involves the recognition, dislocation, and proteolysis of misfolded polypeptides by the 26S proteasome, a multicatalytic enzyme complex localized to the cytoplasm and nucleus (Baumeister et al., 1998; Bonifacino and Weismann, 1998; Brodsky and McCracken, 1999; Plemper and Wolf, 1999) . The ATP-dependent cleavage process is facilitated by multiple ubiquitin attachments to the â‘€ -amino groups of lysine residues of the substrate and catalyzed by a cascade of enzymatic reactions involving ubiquitin-activating (E1) and -conjugating (E2) enzymes in addition to ubiquitin-protein ligases (E3) (Hershko and Ciechanover, 1998) .