A Membrane Protein Complex Mediates Retro-Translocation From the ER Lumen Into the Cytosol

Nature. 2004 Jun 24;429(6994):841-7. doi: 10.1038/nature02656.

Abstract

Elimination of misfolded proteins from the endoplasmic reticulum (ER) by retro-translocation is an important physiological adaptation to ER stress. This process requires recognition of a substrate in the ER lumen and its subsequent movement through the membrane by the cytosolic p97 ATPase. Here we identify a p97-interacting membrane protein complex in the mammalian ER that links these two events. The central component of the complex, Derlin-1, is a homologue of Der1, a yeast protein whose inactivation prevents the elimination of misfolded luminal ER proteins. Derlin-1 associates with different substrates as they move through the membrane, and inactivation of Derlin-1 in C. elegans causes ER stress. Derlin-1 interacts with US11, a virally encoded ER protein that specifically targets MHC class I heavy chains for export from the ER, as well as with VIMP, a novel membrane protein that recruits the p97 ATPase and its cofactor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Amino Acid Sequence
  • Animals
  • Cytosol / metabolism*
  • Dogs
  • Endoplasmic Reticulum / metabolism*
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Macromolecular Substances
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism*
  • Protein Folding
  • Protein Processing, Post-Translational
  • Protein Transport
  • RNA-Binding Proteins / metabolism
  • Selenoproteins
  • Viral Proteins / metabolism

Substances

  • DERL1 protein, human
  • Histocompatibility Antigens Class I
  • Macromolecular Substances
  • Membrane Proteins
  • Nuclear Proteins
  • RNA-Binding Proteins
  • SELENOS protein, human
  • Selenoproteins
  • US11 protein, herpesvirus
  • Viral Proteins
  • Adenosine Triphosphatases
  • p97 ATPase

Associated data

  • RefSeq/NP_060915
  • RefSeq/NP_077271