Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Membrane / metabolism*
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Cystic Fibrosis Transmembrane Conductance Regulator / chemistry*
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Cystic Fibrosis Transmembrane Conductance Regulator / genetics
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Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
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Glycosylation
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HSC70 Heat-Shock Proteins / genetics
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HSC70 Heat-Shock Proteins / metabolism
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HSP90 Heat-Shock Proteins / metabolism
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HeLa Cells
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Homeostasis
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Humans
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Lysosomes / metabolism
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Molecular Chaperones / metabolism
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Mutant Proteins / chemistry
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Mutant Proteins / metabolism
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Protein Conformation
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Protein Folding*
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Protein Stability
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Protein Transport
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RNA, Small Interfering
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Recombinant Proteins / metabolism
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Temperature
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitinated Proteins / chemistry
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Ubiquitinated Proteins / metabolism
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Ubiquitination
Substances
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CFTR protein, human
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HSC70 Heat-Shock Proteins
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HSP90 Heat-Shock Proteins
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HSPA8 protein, human
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Molecular Chaperones
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Mutant Proteins
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RNA, Small Interfering
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Recombinant Proteins
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Ubiquitinated Proteins
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Cystic Fibrosis Transmembrane Conductance Regulator
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STUB1 protein, human
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Ubiquitin-Protein Ligases