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PMID: 20595578 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Peripheral protein quality control removes unfolded CFTR from the plasma membrane.

Science (New York, N.Y.) ·Vol. 329 ·No. 5993 ·2010-08-13 ·Pages 805-10

Okiyoneda T, Barrière H, Bagdány M, Rabeh WM, Du K, Höhfeld J, Young JC, Lukacs GL

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.

MeSH Terms
Cell Membrane/metabolism Cystic Fibrosis Transmembrane Conductance Regulator/chemistry,genetics,metabolism Glycosylation HSC70 Heat-Shock Proteins/genetics,metabolism HSP90 Heat-Shock Proteins/metabolism HeLa Cells Homeostasis Humans Lysosomes/metabolism Molecular Chaperones/metabolism Mutant Proteins/chemistry,metabolism Protein Conformation Protein Folding Protein Stability Protein Transport RNA, Small Interfering Recombinant Proteins/metabolism Temperature Ubiquitin-Protein Ligases/genetics,metabolism Ubiquitinated Proteins/chemistry,metabolism Ubiquitination
Chemicals
CFTR protein, human HSC70 Heat-Shock Proteins HSP90 Heat-Shock Proteins HSPA8 protein, human Molecular Chaperones Mutant Proteins RNA, Small Interfering Recombinant Proteins Ubiquitinated Proteins Cystic Fibrosis Transmembrane Conductance Regulator STUB1 protein, human Ubiquitin-Protein Ligases
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Okiyoneda Tsukasa
Department of Physiology, and Groupe de Recherche Axé sur la Structure des Protéine (GRASP) McGill University, Montreal, Quebec H3G 1Y6, Canada.
Barrière Hervé
Bagdány Miklós
Rabeh Wael M
Du Kai
Höhfeld Jörg
Young Jason C
Lukacs Gergely L
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1191542
Published
2010-08-13
Epub
2010-00-01
Pages
805-10
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC5026491
Subset
IM
Grants
PHS HHS · 103329-1 · United States
PHS HHS · 70306-1 · United States
CIHR · 68825-2 · Canada
CIHR · 103329-1 · Canada
PHS HHS · 68825-2 · United States
CIHR · 70306-1 · Canada
Corrections
CommentIn
PMID: 20705837
External Links
PubMed source DOI: 10.1126/science.1191542 PMC Full Text View journal details
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