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.

The majority of CF-associated point mutations, including the most common, ⌬ F508 CFTR, impair biosynthetic processing by disrupting posttranslational folding at the ER (Welsh and Smith, 1993; Zielenski and Tsui, 1995; Riordan, 1999) . Recently, we have identified a mechanistically distinct category of mutation, caused by premature terminations and frameshift mutations in the CF gene (Haardt et al., 1999) . Although the ER processing of these COOHterminally truncated CFTR variants missing their last 70-82 amino acid residues (T70 and T82 CFTR) is similar to that of the wt form, the biological half-life of the complexglycosylated mutants is sixfold shorter than their wt counterpart (Haardt et al., 1999) . Although the proteolytic elimination mechanism of the processing mutants entrapped in the ER has been extensively studied (Welsh and Smith, 1993; Kopito, 1999; Riordan, 1999) , the cellular processes responsible for the short residence time of the truncated CFTR in post-Golgi compartments remained obscure.