Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane
- Yihong Ye*,
- Yoko Shibata†,
- Marjolein Kikkert‡,
- Sjaak van Voorden‡,
- Emmanuel Wiertz‡, and
- Tom A. Rapoport†,§
- *Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; †Howard Hughes Medical Institute and Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115; and ‡Department of Medical Microbiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
-
Contributed by Tom A. Rapoport, June 24, 2005
Abstract
Misfolded proteins are eliminated from the endoplasmic reticulum (ER) by retrotranslocation into the cytosol, a pathway hijacked by certain viruses to destroy MHC class I heavy chains. The translocation of polypeptides across the ER membrane requires their polyubiquitination and subsequent extraction from the membrane by the p97 ATPase [also called valosin-containing protein (VCP) or, in yeast, Cdc48]. In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP). How the ubiquitination machinery is recruited to the p97/Derlin/VIMP complex is unclear. Here, we report that p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1. During retrotranslocation, a substrate first interacts with Derlin-1 before p97 and other factors join the complex. These data, together with the fact that Derlin-1 is a multispanning membrane protein forming homo-oligomers, support the idea that Derlin-1 is part of a retrotranslocation channel that is associated with both the polyubiquitination and p97-ATPase machineries.
Footnotes
-
↵ § To whom correspondence should be addressed. E-mail: tom_rapoport{at}hms.harvard.edu.
-
Author contributions: Y.Y., E.W., and T.A.R. designed research; Y.Y., Y.S., M.K., and S.v.V. performed research; Y.Y., M.K., E.W., and T.A.R. analyzed data; and Y.Y. and T.A.R. wrote the paper.
-
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on May 3, 2005.
-
Abbreviations: ER, endoplasmic reticulum; VIMP, VCP-interacting membrane protein.
-
See accompanying Profile on page 14129.
- Copyright © 2005, The National Academy of Sciences
