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.

Since the retrograde translocation of the T70 CFTR via the translocon is unlikely to occur in post-Golgi compartments (Xiong et al., 1999) , the coordinated action of multiple proteolytic systems is invoked to resolve the topological problem of disposing transmembrane segments and exofacial loops of the T70 CFTR. Degradation appears to be initiated by the unfolding of cytosolic domains in a proteasome-dependent manner. The biochemical as well as functional rescue of cell surface resident T70, but not wt CFTR (data not shown), by proteasome inhibitors substantiate this hypothesis. Whereas the initial cleavage of the mature wt CFTR, as opposed to mutant, relies on the activity of lysosmal proteases, subsequent degradation of wt and T70 CFTR converges in endolysosomes, demonstrated by their overlapping proteolytic fragmentation pattern in the presence of cathepsin inhibitors (Fig. 3 B) .