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.
Christianson
John C
JC
Department of Biological Sciences & Bio-X Program, Stanford University, Lorry Lokey Bldg, 337 Campus Drive, Stanford, CA 94305, USA.
Shaler
Thomas A
TA
Tyler
Ryan E
RE
Kopito
Ron R
RR
D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D037102:Lectins; D008562:Membrane Glycoproteins / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation; D009363:Neoplasm Proteins / Q000502:physiology*; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000737:chemistry; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
D037102:Lectins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C098898:OS9 protein, human; D011506:Proteins; D017527:Receptor, IGF Type 2; C117384:SEL1L protein, human; D025801:Ubiquitin; D000515:alpha 1-Antitrypsin; C053387:endoplasmin; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases