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.

If deletion of the COOH terminus destabilizes CFTR exclusively in post-Golgi compartments, retention of folded T70 CFTR in the ER would protect against degradation. Taking advantage of the fact that BFA can provoke the accumulation of folded CFTR in the ER without interfering with ERAD, the stability of folded T70 CFTR was measured after the elimination of the immature core-glycosylated form (Fig. 4 E) . The turnover of the folded core-glycosylated T70 CFTR was fourfold slower ( t 1/2 ‫ف‬ 7 h) than that of the complex-glycosylated T70 CFTR ( t 1/2 ‫ف‬ 1.8 h; Fig. 4 F) . In contrast, ER retention only marginally increased the half-life of the wt CFTR ( t 1/2 ‫ف‬ 14 h vs. ‫11ف‬ h; Fig. 4 G) , underlining our previous observations that destabilization of T70 CFTR primarily manifests at the distal stage of the secretory pathway. Similar stabilization was observed upon retaining the complex-glycosylated T70 CFTR in the distal Golgi region by aluminum fluoride (Benharouga, M., and G.L. Lukacs, unpublished observation).