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.
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Acknowledgements
We thank R. Prywes for ATF6 plasmid, the Taplin Mass Spectrometry facility (Harvard Medical School) for protein identification, and the Nikon imaging facility (Harvard Medical School) for assistance in microscopy. We thank E. Hartmann for help with sequence analysis, D. Flierman for help with the Derlin-1 immunoprecipitation, and C. Shamu, D. Finley and K. Cannon for critical reading of the manuscript. Y.Y. is supported by a Helen Hay Whitney fellowship and T.A.R. by an NIH grant. C.Y is supported by an NIH fellowship and D.R. by NIH grants and the Ellison Medical Foundation. T.A.R. is a Howard Hughes Medical Institute investigator.
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Supplementary information
Supplementary Figure S1
Phylogenetic analysis of Der1/Derlin family members. (JPG 60 kb)
Supplementary Figure S2
Amino acid sequence of VIMP. (DOC 19 kb)
Supplementary Figure S3
Specificity of the Derlin-1 and VIMP antibodies. (JPG 58 kb)
Supplementary Figure S4
VIMP associates with p97 in transfected cells. (JPG 64 kb)
Supplementary Figure S5
Gel filtration of the purified cytosolic domain of VIMP (VIMPc). (JPG 23 kb)
Supplementary Figure S6
US11 and Derlin-1 co-localize in transfected COS cells. (JPG 246 kb)
Supplementary Figure S7
Overexpression of VIMP alters ER morphology. (JPG 203 kb)
Supplementary Table 1
Identification of p97-interacting proteins (DOC 19 kb)
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Ye, Y., Shibata, Y., Yun, C. et al. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429, 841–847 (2004). https://doi.org/10.1038/nature02656
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DOI: https://doi.org/10.1038/nature02656
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