The ubiquitin–proteasome (Ub-Pr) degradation pathway regulates many cellular activities1,2, but how ubiquitinated substrates are targeted to the proteasome is not understood. We have shown previously that valosin-containing protein (VCP) physically and functionally targets the ubiquitinated nuclear factor κB inhibitor, IκBα to the proteasome for degradation3. VCP4 is an abundant and a highly conserved member of the AAA (ATPases associated with a variety of cellular activities) family5,6,7. Besides acting as a chaperone in membrane fusions, VCP has been shown to have a role in a number of seemingly unrelated cellular activities. Here we report that loss of VCP function results in an inhibition of Ub-Pr-mediated degradation and an accumulation of ubiquitinated proteins. VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. Furthermore, its N-terminal domain is required in Ub-Pr-mediated degradation. We conclude that VCP is a multi-ubiquitin chain-targeting factor that is required in the degradation of many Ub-Pr pathway substrates, and provide a common mechanism that underlies many of the functions of VCP.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hochstrasser, M. Annu. Rev. Genet. 30, 405–439 (1996).
Hershko, A., Ciechanover, A. & Varshavsky, A. Nature Med. 6, 1073–1081 (2000).
Dai, R.-M., Chen, E., Longo, D. L., Gorbea, C. M. & Li, C.-C. H. J. Biol. Chem. 273, 3562–3573 (1998).
Egerton, M. et al. EMBO J. 11, 3533–3540 (1992).
Patel, S. & Latterich, M. Trends Cell Biol. 8, 65–71 (1998).
Neuwald, A. F., Aravind, L., Spouge, J. L. & Koonin, E. V. Genome Res 9, 27–43 (1999).
Zwickl, P. & Baumeister, W. Nature Cell Biol. 1, E97–E98 (1999).
Coux, O., Tanaka, K. & Goldberg, A. L. Annu. Rev. Biochem. 65, 801–847 (1996).
Baumeister, W., Walz, J., Zuhl, F. & Seemuller, E. Cell 92, 367–380 (1998).
DeMartino, G. N. & Slaughter, C. A. J. Biol. Chem. 274, 22123–22126 (1999).
Deveraux, Q., Ustrell, V., Pickart, C. & Rechsteiner, M. J. Biol. Chem. 269, 7059–7061 (1994).
Van Nocker, S. et al. Mol. Cell Biol. 11, 6020–6028 (1996).
Fu, H. et al. J. Biol. Chem. 273, 1970–1981 (1998).
Yen, C.-H. et al. J. Immunol. 165, 6372–6380 (2000).
Moir, D., Stewart, S. E., Osmond, B. C. & Botstein, D. Genetics 100, 547–563 (1982).
Ghislain, M., Dohmen, R. J., Levy, F. & Varshavsky, A. EMBO J. 15, 4884–4899 (1996).
Chen, E. et al. J. Biol. Chem. 273, 35201–35207 (1998).
Clurman, B. E., Sheaff, R. J., Thress, K., Groudine, M. & Roberts, J. M. Genes Dev. 10, 1979–1990 (1996).
Won, K. A. & Reed, S. I. EMBO J. 15, 4182–4193 (1996).
Chau, V. et al. Science 243, 1576–1583 (1989).
Pickart, C. M. FASEB J. 11, 1055–1066 (1997).
Thrower, J. S., Hoffman, L., Rechsteiner, M. & Pickart, C. M. EMBO J. 19, 94–102 (2000).
Young, P., Deveraux, Q., Beal, R. E., Pickart, C. M. & Rechsteiner, M. J. Biol. Chem. 273, 5461–5467 (1998).
Kondo, H. et al. Nature 388, 75–78 (1997).
Leon, A. & McKearin, D. Mol. Biol. Cell 10, 3825–3834 (1999).
Meyer, H. H., Shorter, J. G., Seemann, J., Pappin, D. & Warren, G. EMBO J. 19, 2181–2192 (2000).
Koegl, M. et al. Cell 96, 635–644 (1999).
Golbik, R., Lupas, A. N., Koretke, K. K., Baumeister, W. & Peters J. Biol. Chem. 380, 1049–1062 (1999).
Beckwith, M, Longo, D. L., O' Connell, C. D., Moratz, C. M. & Urba, W. J. J. Natl Cancer Inst. 82, 501–509 (1990).
Egerton, M. & Samelson L. E. J. Biol. Chem. 269, 11435–11441 (1994).
We thank C. Pickart for Ub4 chains and Ub antiserum; M. Rechsteiner and C. Gorbea for S5a constructs; D. Botstein for cdc48-1 and wild-type strains; L. Samelson for GST–VCP plasmid; and H. Fu and R. Vierstra for initial binding analyses. We are grateful to J. Strathern for assistance with yeast analyses. We also thank M. Rechsteiner, C. Gorbea and Q. Wang for comments on the manuscript; and S. Gottesman, S. Wickner and M. Maurizi for helpful discussions. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was funded by the NCI under a grant to SAIC.
Figure S1Structure-function analyses in multi-Ub chain binding and in vitro Ub-Pr degradation. (PDF 590 kb)
About this article
DNA Repair (2019)
Calcified Tissue International (2019)
VAMP associated proteins are required for autophagic and lysosomal degradation by promoting a PtdIns4P-mediated endosomal pathway
Neuropathology and Applied Neurobiology (2019)