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 COOH-terminal tail of CFTR might confer stability to the mature CFTR by several mechanisms or a combination thereof. Deletion of the COOH terminus, comprising a postsynaptic density-95, disc-large, and zonula occludens-1-binding motif ( 1476 DTRL) that ensures the association of CFTR with EBP-50 (for ezrin-radixin-moesinbinding phosphoprotein 50) both in vitro and in vivo may facilitate lysosomal degradation by compromising endosomal sorting for recycling (Hall et al., 1998; Short et al., 1998; Moyer et al., 2000) . A similar paradigm was proposed for the accelerated degradation of the ␤ 2 -adrenergic receptor upon preventing its binding to EBP-50 (Cao et al., 1999) . However, this possibility appears to be unlikely, since the steady state expression level and turnover rate of a CFTR variant lacking the COOH-terminal 26 amino acid residues are normal (Mickle et al., 1998; Haardt et al., 1999) . Neither can aggregation of T70 CFTR at the trans-Golgi or at early endosomes target the mutant for lysosomal degradation. Finally, the absence of the COOH-terminal tail may structurally destabilize the folded CFTR, increasing the portion of nonnative molecules that are susceptible to proteolysis.