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Originally published In Press as doi:10.1074/jbc.M209275200 on October 9, 2002

J. Biol. Chem., Vol. 277, Issue 51, 49952-49957, December 20, 2002
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Ablation of Internalization Signals in the Carboxyl-terminal Tail of the Cystic Fibrosis Transmembrane Conductance Regulator Enhances Cell Surface Expression*

Krisztina PeterDagger §, Karoly VargaDagger §, Zsuzsa BebokDagger §, Carmel M. McNicholas-Bevensee||, Lisa SchwiebertDagger §||, Eric J. Sorscher**§, Erik M. SchwiebertDagger §||, and James F. CollawnDagger §Dagger Dagger

From the Departments of Dagger  Cell Biology, || Physiology and Biophysics, and ** Medicine and the § Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that undergoes endocytosis through clathrin-coated pits. Previously, we demonstrated that Y1424A is important for CFTR endocytosis (Prince, L. S., Peter, K., Hatton, S. R., Zaliauskiene, L., Cotlin, L. F., Clancy, J. P., Marchase, R. B., and Collawn, J. F. (1999) J. Biol. Chem. 274, 3602-3609). Here we show that a second substitution in the carboxyl-terminal tail of CFTR, I1427A, on Y1424A background more than doubles CFTR surface expression as monitored by surface biotinylation. Internalization assays indicate that enhanced surface expression of Y1424A,I1427A CFTR is caused by a 76% inhibition of endocytosis. Patch clamp recording of chloride channel activity revealed that there was a corresponding increase in chloride channel activity of Y1424A,I1427A CFTR, consistent with the elevated surface expression, and no change in CFTR channel properties. Y14124A showed an intermediate phenotype compared with the double mutation, both in terms of surface expression and chloride channel activity. Metabolic pulse-chase experiments demonstrated that the two mutations did not affect maturation efficiency or protein half-life. Taken together, our data show that there is an internalization signal in the COOH terminus of CFTR that consists of Tyr1424-X-X-Ile1427 where both the tyrosine and the isoleucine are essential residues. This signal regulates CFTR surface expression but not CFTR biogenesis, degradation, or chloride channel function.

* This work was supported in part by a fellowship from the Research Development Program of the Cystic Fibrosis Foundation (CFF) (to K. P. and K. V.), Grants COLLAWOOGO from the CFF and DK 60065 from the National Institutes of Health (to J. F. C.), Grant DK 54367 from the National Institutes of Health (to E. M. S.), and a grant from the Research Development Program of the CFF and the National Institutes of Health (to E. J. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

Dagger Dagger To whom correspondence should be addressed: Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama, MCLM 350, 1918 University Blvd., Birmingham, AL 35294-0005. Tel.: 205-934-1002; E-mail: jcollawn@uab.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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