Therapeutic efforts to restore biosynthetic processing of the cystic fibrosis transmembrane
conductance regulator lacking the F508 residue (DeltaF508CFTR) are hampered by ubiquitin-dependent
lysosomal degradation of nonnative, rescued DeltaF508CFTR 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.
