E3 ubiquitin ligase that recognizes sugar chains

Nature. 2002 Jul 25;418(6896):438-42. doi: 10.1038/nature00890.

Abstract

N-glycosylation of proteins in the endoplasmic reticulum (ER) has a central role in protein quality control. Here we report that N-glycan serves as a signal for degradation by the Skp1-Cullin1-Fbx2-Roc1 (SCF(Fbx2)) ubiquitin ligase complex. The F-box protein Fbx2 (ref. 4) binds specifically to proteins attached to N-linked high-mannose oligosaccharides and subsequently contributes to ubiquitination of N-glycosylated proteins. Pre-integrin beta 1 is a target of Fbx2; these two proteins interact in the cytosol after inhibition of the proteasome. In addition, expression of the mutant Fbx2 Delta F, which lacks the F-box domain that is essential for forming the SCF complex, appreciably blocks degradation of typical substrates of the ER-associated degradation pathway. Our results indicate that SCF(Fbx2) ubiquitinates N-glycosylated proteins that are translocated from the ER to the cytosol by the quality control mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cysteine Endopeptidases / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Endoplasmic Reticulum / metabolism
  • Glycoproteins / chemistry*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Glycosylation
  • Humans
  • Integrin beta1 / metabolism
  • Leupeptins / pharmacology
  • Ligases / chemistry*
  • Ligases / metabolism*
  • Macromolecular Substances
  • Mannose / metabolism
  • Mice
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism
  • Polysaccharides / chemistry*
  • Polysaccharides / metabolism*
  • Proteasome Endopeptidase Complex
  • Protein Binding / drug effects
  • Protein Precursors / metabolism
  • Ribonucleases / chemistry
  • Ribonucleases / metabolism
  • Substrate Specificity
  • Transfection
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases
  • alpha-Fetoproteins / chemistry
  • alpha-Fetoproteins / metabolism

Substances

  • CFTR protein, human
  • Glycoproteins
  • Integrin beta1
  • Leupeptins
  • Macromolecular Substances
  • Multienzyme Complexes
  • Polysaccharides
  • Protein Precursors
  • Ubiquitin
  • alpha-Fetoproteins
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Ubiquitin-Protein Ligases
  • Ribonucleases
  • ribonuclease B
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Ligases
  • Mannose
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde