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.

Although the truncated CFTR is one of the first mutant plasma membrane proteins subjected to sequential proteasomal and lysosomal breakdown, the coordinated action of these proteolytic systems is not without precedent. Although both lysosomes and proteasomes are involved in the constitutive and ligand-induced disposal of con-nexin43, the renal Na/P i cotransporter, and the PDGF ␤ receptor, respectively (Mori et al., 1995; Laing et al., 1997; Pfister et al., 1998) , the recognition mechanism of these substrates by the proteasome remains unknown. Considering that deletion of the COOH-terminal tail appears to destabilize CFTR structurally, we propose that the ubiquitinproteasome pathway may play a role in the recognition and elimination of not only the T70 CFTR, but also other nonnative or partially unfolded plasma membrane proteins.