Research Article

Peripheral Protein Quality Control Removes Unfolded CFTR from the Plasma Membrane

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Science  13 Aug 2010:
Vol. 329, Issue 5993, pp. 805-810
DOI: 10.1126/science.1191542

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Peripheral Quality Control

Protein misfolding diseases often lead to the retention and degradation of important proteins within the endoplasmic reticulum (ER). Strategies to reduce the stringency of ER quality control that allow the proteins to carry on through the secretory pathway to reach their destination at the cell surface have shown some promise. Okiyoneda et al. (p. 805, published online 1 July; see the Perspective by Hutt and Balch) wanted to understand how, even if a protein reaches its destination, it may still be subjected to a second level of quality control and be cleared from the plasma membrane. Using functional small-interfering RNA screens in cells expressing the common cystic fibrosis mutation F508CFTR, the authors identified a pair of chaperones that promoted clearance of defective proteins from the plasma membrane. This peripheral quality-control step will also need to be overcome to increase the effectiveness of strategies to overcome protein misfolding disorders.

Abstract

Therapeutic efforts to restore biosynthetic processing of the cystic fibrosis transmembrane conductance regulator lacking the F508 residue (ΔF508CFTR) are hampered by ubiquitin-dependent lysosomal degradation of nonnative, rescued ΔF508CFTR 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.

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