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.

Trafficking defects have been recognized as the underlying mechanism in a growing number of genetic diseases, including cystic fibrosis (CF), diabetes insipidus, and ␣ 1 antitrypsin deficiency (Thomas et al., 1995; Bonifacino and Weismann, 1998; Hershko and Ciechanover, 1998; Aridor and Balch, 1999; Kopito, 1999; Schwartz and Ciechanover, 1999) . CF, the most prevalent recessive genetic disorder in the caucasian population, is caused by the dysfunction of the CF transmembrane conductance regulator (CFTR), a member of the ATP-binding cassette transport protein family (Riordan et al., 1989; Rommens et al., 1989) . CFTR is a cAMP-stimulated Cl Ϫ channel, residing predominantly at the cell surface and, less abundantly, in the endosomal compartment (Bradbury, 1999) . The channel consists of two homologous halves, each comprised of six transmembrane helices and a nucleotide binding domain (NBD1 and NBD2), which are connected by the regulatory domain (Riordan et al., 1989) . This complex, multidomain structure conceivably renders the posttranslational folding of wild-type (wt) CFTR inefficient. Approximately 70% of the newly synthesized wt CFTR is trapped in the ER as core-glycosylated folding intermediate (apparent molecular weight ‫ف‬ 150, 000) and degraded with a t 1/2 of ‫ف‬ 30 min by the ERAD. Proteasome activity is responsible, at least in part, for the degradation of the co-and posttranslationally ubiquitinated and incompletely folded CFTR at the ER (Jensen et al., 1995; Ward et al., 1995; Xiong et al., 1999) . However, inhibition of proteasomes has failed to promote the processing of core-glycosylated wt as well as the ⌬ F508 CFTR (Jensen et al., 1995; Ward et al., 1995) .