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.

In mammalian cells, aggregated furin, incompletely assembled Golgi coronavirus E1, and mutant connexin32 are destined for lysosomal degradation from the Golgi region without reaching the cell surface (Armstrong et al., 1990; Wolins et al., 1997; VanSlyke et al., 2000) . A post-ER quality control mechanism appears to be responsible for targeting and vacuolar degradation of mutant plasma membrane ATPase, the late Golgi protease Kex2, and a model protein, comprising the secretory invertase and the NH 2 terminus of the lambda repressor in Saccharomyces cerevisiae (Wilcox et al., 1992; Chang and Fink, 1995; Hong et al., 1996) . Aggregation of unoccupied class II major histocompatibility complex molecules and cross-linking of cell surface membrane proteins, such as the transferrin receptor, can evoke preferential lysosomal targeting and degradation (Weissman et al., 1986; Amigorena et al., 1995) . Although most of these examples illustrate that nonnative membrane protein is targeted for lysosomal proteolysis either before their arrival to the cell surface or after their internalization, the complex-glycosylated truncated CFTR has a distinct intracellular fate. We presented compelling evidence indicating that the dramatically decreased expression level and residence time of the complex-glycosylated truncated CFTR cannot be attributed to missorting for lysosomal degradation at the trans-Golgi or endosomal compartment. Instead, the truncated CFTR is targeted to the plasma membrane with comparable efficiency to its wt counterpart (Fig. 1) . The turnover of the total and cell surface biotinylated T70 CFTR pools was insensitive to inhibitors of endolysosomal proteases. In contrast, weak bases and cathepsin inhibitors stabilized the full-length form and degradation intermediates of wt CFTR in transfected cells as well as in epithelia, highlighting the multiple role of endolysosomal proteolysis in the turnover of wt CFTR (Figs. 2 and 3) .