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OS-9 and GRP94 deliver mutant α1-antitrypsin to the Hrd1–SEL1L ubiquitin ligase complex for ERAD

Nature Cell Biology volume 10, pages 272282 (2008) | Download Citation

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Abstract

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 α1-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.

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Acknowledgements

We thank J. Weissman, I. Biunno, V. Chau, C. Nicchitta, H. Ploegh, G. Semenza, J. Kelly and E. Wiertz for reagents and technical advice, members of the Kopito lab for helpful discussion, and S. Duttler and J. Olzmann for critical reading of the manuscript. This work was supported by grants from NIDDK, NIGMS, and the Cystic Fibrosis Foundation. JCC was supported by a postdoctoral fellowship from Cystic Fibrosis Research, Inc.

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Affiliations

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

    • John C. Christianson
    • , Ryan E. Tyler
    •  & Ron R. Kopito
  2. PPD, 1505 O'Brien Drive, Menlo Park, CA 94025, USA.

    • Thomas A. Shaler

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Contributions

J. C. C. performed all experiments and data analysis, with the exception of Table 1 and Supplementary Information, Fig. 4, which were carried out by T. A. S. and R. E. M.; J. C. C. and R. R. K. wrote the manuscript.

Corresponding author

Correspondence to Ron R. Kopito.

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    Supplementary Information

    Supplementary figures S1, S2, S3, S4, S5 and table S1

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https://doi.org/10.1038/ncb1689

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