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 key question that remains to be resolved is whether ubiquitination is a prerequisite for proteasome-dependent degradation of the mutant CFTR from the cell surface or endosomal compartment. Several tyrosine kinase and G protein-coupled receptors have been observed to undergo ligand-induced ubiquitination and downregulation via lysosomal and/or proteasomal degradation (Bonifacino and Weismann, 1998; Hershko and Ciechanover, 1998; Hicke, 1999; Strous and Govers, 1999) . Ubiquitination also ap-pears to be necessary and sufficient to induce the internalization and downregulation of plasma membrane receptors and transporters (e.g., FUR4, GAP1, STE2, STE3, and STE6) via vacuolar proteolysis in yeast (Hicke, 1999) . The constitutive downregulation of the epithelial sodium channel (ENaC), in association with the Nedd4 ubiquitinligase, was proposed to follow a similar degradation route, in contrast to the unassembled subunits of the channel, which were degraded by a proteasome-dependent mechanism at the ER (Staub et al., 1997) .