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 both covalent and noncovalent attachment of ubiquitins can serve as a degradation signal of plasma membrane proteins via internalization Shih et al., 2000) , one possible scenario is that augmented ubiquitination of CFTR, or an associated protein, facilitates the internalization of the mutant. On the other hand, in light of multiple tyrosine-and dileucine-based endocytic signals in CFTR, ubiquitin attachment may not be a prerequisite for endocytosis Prince et al., 1999; Hu et al., 2001) . Consistent with the dispensable nature of ubiquitination, downregulation of the ␤ 2 -adrenergic and mutant m2-muscarinic receptors can proceed without endocytosis, presumably by direct association with proteasome and/or other, presently unidentified proteases (Jockers et al., 1999; Wilson and Limbird, 2000) . The recognition that both 26S proteasome and P700 subunit are able to degrade nonnative polypeptides lacking polyubiquitin conjugates supports the notion that a ubiquitin-independent degradation mechanism cannot be ruled out (Murakami, 1992; Braun et al., 1999; Sheaff et al., 2000; Strickland et al., 2000) . Importantly, these degradation pathways are not mutually exclusive and may function in parallel.