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.

We have demonstrated previously that the steady state expression level of the complex-glycosylated CFTR missing its last 70, 82, or 98 amino acids (designated as T70, T82, and T98 CFTR) was decreased by ‫ف‬ 90% compared with wt CFTR in heterologous expression systems (Haardt et al., 1999) . In contrast, deletion of the last 26 amino acid residues (T26 CFTR) was without effect (Mickle et al., 1998; Haardt et al., 1999) . It was also shown that neither the translational rate nor the biosynthetic maturation of the T70 and T82 CFTR was significantly impaired at the ER in transient COS-1 (Haardt et al., 1999) or in stable BHK expression systems (Benharouga, M., and G.L. Lukacs, unpublished data). We proposed that, in contrast to the most prevalent CF-associated processing mutations (e.g., ⌬ F508 CFTR), which compromise the biogenesis of CFTR, destabilization of the mature form at distal stages of the biosynthetic or endocytic pathway accounts for the phenotypic manifestation of truncated CFTR (Haardt et al., 1999) .