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Science 329 (5993): 805-810

Copyright © 2010 by the American Association for the Advancement of Science

Peripheral Protein Quality Control Removes Unfolded CFTR from the Plasma Membrane

Tsukasa Okiyoneda,1 Hervé Barrière,1 Miklós Bagdány,1 Wael M. Rabeh,1 Kai Du,1 Jörg Höhfeld,2 Jason C. Young,3 Gergely L. Lukacs1,*

Abstract: Therapeutic efforts to restore biosynthetic processing of the cystic fibrosis transmembrane conductance regulator lacking the F508 residue ({Delta}F508CFTR) are hampered by ubiquitin-dependent lysosomal degradation of nonnative, rescued {Delta}F508CFTR from the plasma membrane. Here, functional small interfering RNA screens revealed the contribution of chaperones, cochaperones, and ubiquitin-conjugating and -ligating enzymes to the elimination of unfolded CFTR from the cell surface, as part of a peripheral protein quality-control system. Ubiquitination of nonnative CFTR was required for efficient internalization and lysosomal degradation. This peripheral protein quality-control mechanism probably participates in the preservation of cellular homeostasis by degrading damaged plasma membrane proteins that have escaped from the endoplasmic reticulum quality control or are generated by environmental stresses in situ.

1 Department of Physiology, and Groupe de Recherche Axé sur la Structure des Protéine (GRASP) McGill University, Montreal, Quebec H3G 1Y6, Canada.
2 Cell Biology Institute, University Bonn, D-53121 Bonn, Germany.
3 Department of Biochemistry, and Groupe de Recherche Axé sur la Structure des Protéine (GRASP) McGill University, Montreal, Quebec H3G 1Y6, Canada.

* To whom correspondence should be addressed. E-mail: gergely.lukacs{at}

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