TY  - JOUR
AB  - The ClC-5 chloride channel resides mainly in vesicles of the endocytotic pathway and contributes to their acidification. Its disruption in mice entails a broad defect in renal endocytosis and causes secondary changes in calciotropic hormone levels. Inactivating mutations in Dent's disease lead to proteinuria and kidney stones. Possibly by recycling, a small fraction of ClC-5 also reaches the plasma membrane. Here we identify a carboxyl-terminal internalization motif in ClC-5. It resembles the PY motif, which is crucial for the endocytosis and degradation of epithelial Na+ channels. Mutating this motif increases surface expression and currents about 2-fold. This is probably because of interactions with WW domains, because dominant negative mutants of the ubiquitin-protein ligase WWP2 increased surface expression and currents of ClC-5 only when its PY motif was intact. Stimulating endocytosis by expressing rab5 or its GTPase-deficient Q79L mutant decreased WT ClC-5 currents but did not affect channels with mutated motifs. Similarly, decreasing endocytosis by expressing the inactive S34N mutant of rab5 increased ClC-5 currents only if its PY-like motif was intact. Thus, the endocytosis of ClC-5, which itself is crucial for the endocytosis of other proteins, depends on the interaction of a carboxyl-terminal internalization signal with ubiquitin-protein ligases containing WW domains.
DA  - 2001
DO  - 10.1074/jbc.M010642200
LA  - eng
IS  - 15
M2  - 12049
PY  - 2001
SN  - 0021-9258
SP  - 12049-12054
T2  - Journal of Biological Chemistry
TI  - An Internalization Signal in ClC-5, an Endosomal Cl−Channel Mutated in Dent's Disease
UR  - https://nbn-resolving.org/urn:nbn:de:0070-pub-29533636
Y2  - 2024-11-22T02:37:10
ER  -