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.

A combination of transcriptional, cotranslational, and posttranslational mechanisms contributes to the ER quality control, preventing misfolded secretory and membrane proteins from traversing the secretory pathway (Ellgaard et al., 1999; Wickner et al., 1999; Mori, 2000) . Nevertheless, several examples demonstrate that the fidelity of the ER quality control is far from perfect. Nonfunctional polypeptides can escape ER retention, whereas mutants with partially or fully preserved biological function are being trapped, causing severe human diseases such as CF and alpha 1-protease inhibitor deficiency (Thomas et al., 1995; Zielenski and Tsui, 1995; Aridor and Balch, 1999; Schwartz and Ciechanover, 1999) . Nonnative polypeptides could also be generated in post-ER compartments as a result of unfolding upon environmental stresses or mutations that compromise the native form stability (Goldenberg, 1992; Pacifici et al., 1993; Parsell and Lindquist, 1993; Sitte et al., 1998) . Little is known about the mechanism responsible for the degradation of abnormal membrane proteins from post-ER compartments.