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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.

Original publication

DOI

10.1038/ncb1689

Type

Journal article

Journal

Nature cell biology

Publication Date

03/2008

Volume

10

Pages

272 - 282

Addresses

Department of Biological Sciences & Bio-X Program, Stanford University, Lorry Lokey Bldg, 337 Campus Drive, Stanford, CA 94305, USA.

Keywords

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