COOH-terminal truncations promote proteasome-dependent degradation of mature cystic fibrosis transmembrane conductance regulator from post-Golgi compartments

Impaired biosynthetic processing of the cys tic fibrosis (CF) transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel, constitut es the most common cause of CE Recently, we have identified a distinct cate gory of mutation, caused by premature stop codons and frameshift mutations, which manifests in diminished expression of COOH-terminally truncated CFTR at the cell surface. Although the biosynthetic processing and plasma membr ane targeting of truncated CFTRs are preserved. the turnover of the complex -glycosylated mutant is sixfold faster than its wild-type (wt) counterpart. Destabilization of the truncated CFTR coincides with its enhanced suscepti bility to proteasome-dependent degradation from post-Golgi compartments glo bally, and the plasma membrane specifically, determined by pulse-chase anal ysis in conjunction with cell surface biotinylation. Proteolytic cleavage o f the full-length complex-glycosylated wt and degradation intermediates der ived from both T70 and wt CFTR requires endolysosomal proteases. The enhanc ed protease sensitivity in vitro and the decreased thermostability of the c omplex-glycosylated T70 CFTR in vivo suggest that structural destabilizatio n may account for the increased proteasome susceptibility and the short res idence time at the cell surface. These in turn are responsible, at least in part, for the phenotypic manifestation of CE We propose that the proteasom e-ubiquitin pathway may be involved in the peripheral quality control of ot her. partially unfolded membrane proteins as well.