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.

Here we show that deletion of the COOH terminus renders the complex-glycosylated truncated CFTR highly susceptible to proteasome-dependent proteolysis at post-Golgi compartments, including the plasma membrane. Structural destabilization, demonstrated by increased pro-tease susceptibility in vitro and diminished thermostability of the complex-glycosylated mutants in vivo, may serve as signal for premature proteolysis. In contrast, lysosomal proteolysis appears to represent the rate-limiting step in the degradation of the complex-glycosylated wt CFTR. These results reveal a novel aspect of the proteasomedependent degradation pathway in the elimination of nonnative CFTR after its escape from the ER quality control.