Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes. Academic Article uri icon

Overview

abstract

  • To investigate the degradation mechanism of misfolded membrane proteins from the cell surface, we used mutant cystic fibrosis transmembrane conductance regulators (CFTRs) exhibiting conformational defects in post-Golgi compartments. Here, we show that the folding state of CFTR determines the post-endocytic trafficking of the channel. Although native CFTR recycled from early endosomes back to the cell surface, misfolding prevented recycling and facilitated lysosomal targeting by promoting the ubiquitination of the channel. Rescuing the folding defect or down-regulating the E1 ubiquitin (Ub)-activating enzyme stabilized the mutant CFTR without interfering with its internalization. These observations with the preferential association of mutant CFTRs with Hrs, STAM-2, TSG101, hVps25, and hVps32, components of the Ub-dependent endosomal sorting machinery, establish a functional link between Ub modification and lysosomal degradation of misfolded CFTR from the cell surface. Our data provide evidence for a novel cellular mechanism of CF pathogenesis and suggest a paradigm for the quality control of plasma membrane proteins involving the coordinated function of ubiquitination and the Ub-dependent endosomal sorting machinery.

authors

  • Sharma, Manu
  • Pampinella, Francesca
  • Nemes, Csilla
  • Benharouga, Mohamed
  • So, Jeffrey
  • Du, Kai
  • Bache, Kristi G
  • Papsin, Blake
  • Zerangue, Noa
  • Stenmark, Harald
  • Lukacs, Gergely L

publication date

  • March 8, 2004

Research

keywords

  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Endosomes
  • Protein Conformation
  • Protein Folding
  • Protein Transport

Identity

PubMed Central ID

  • PMC2172283

Scopus Document Identifier

  • 12144287602

Digital Object Identifier (DOI)

  • 10.1083/jcb.200312018

PubMed ID

  • 15007060

Additional Document Info

volume

  • 164

issue

  • 6