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OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD.

Terminally misfolded or unassembled proteins in the early secretory pathway are degraded by a ubiquitin- and proteasome-dependent process known as ER-associated degradation (ERAD). How substrates of this pathway are recognized within the ER and delivered to the cytoplasmic ubiquitin-conjugating machinery is unknown. We report here that OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to ERAD substrates and, through the SEL1L adaptor, to the ER-membrane-embedded ubiquitin ligase Hrd1. Both proteins contain conserved mannose 6-phosphate receptor homology (MRH) domains, which are required for interaction with SEL1L, but not with substrate. OS-9 associates with the ER chaperone GRP94 which, together with Hrd1 and SEL1L, is required for the degradation of an ERAD substrate, mutant alpha(1)-antitrypsin. These data suggest that XTP3-B and OS-9 are components of distinct, partially redundant, quality control surveillance pathways that coordinate protein folding with membrane dislocation and ubiquitin conjugation in mammalian cells.

Pubmed ID: 18264092

Authors

  • Christianson JC
  • Shaler TA
  • Tyler RE
  • Kopito RR

Journal

Nature cell biology

Publication Data

March 3, 2008

Associated Grants

  • Agency: NIGMS NIH HHS, Id: R01 GM074874
  • Agency: NIGMS NIH HHS, Id: R01 GM074874-04

Mesh Terms

  • Endoplasmic Reticulum
  • Gene Expression Regulation
  • Humans
  • Lectins
  • Membrane Glycoproteins
  • Models, Biological
  • Mutation
  • Neoplasm Proteins
  • Protein Binding
  • Protein Denaturation
  • Protein Folding
  • Proteins
  • Receptor, IGF Type 2
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • alpha 1-Antitrypsin