Skip to main content
SpringerLink
Log in

Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin–proteasome degradation

  • Brief Communication
  • Published:

From Nature Cell Biology

View current issue Submit your manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1: Accumulation of ubiquitinylated proteins in cold-treated cdc48-1 cells.
Figure 2: Requirement for VCP in the Ub-Pr-mediated degradation of cyclin E.
Figure 3: VCP as a multi-Ub chain-binding protein.

Similar content being viewed by others

References

  1. Hochstrasser, M. Annu. Rev. Genet. 30, 405–439 (1996).

    Article  CAS  Google Scholar 

  2. Hershko, A., Ciechanover, A. & Varshavsky, A. Nature Med. 6, 1073–1081 (2000).

    Article  CAS  Google Scholar 

  3. Dai, R.-M., Chen, E., Longo, D. L., Gorbea, C. M. & Li, C.-C. H. J. Biol. Chem. 273, 3562–3573 (1998).

    Article  CAS  Google Scholar 

  4. Egerton, M. et al. EMBO J. 11, 3533–3540 (1992).

    Article  CAS  Google Scholar 

  5. Patel, S. & Latterich, M. Trends Cell Biol. 8, 65–71 (1998).

    Article  CAS  Google Scholar 

  6. Neuwald, A. F., Aravind, L., Spouge, J. L. & Koonin, E. V. Genome Res 9, 27–43 (1999).

    CAS  Google Scholar 

  7. Zwickl, P. & Baumeister, W. Nature Cell Biol. 1, E97–E98 (1999).

    Article  CAS  Google Scholar 

  8. Coux, O., Tanaka, K. & Goldberg, A. L. Annu. Rev. Biochem. 65, 801–847 (1996).

    Article  CAS  Google Scholar 

  9. Baumeister, W., Walz, J., Zuhl, F. & Seemuller, E. Cell 92, 367–380 (1998).

    Article  CAS  Google Scholar 

  10. DeMartino, G. N. & Slaughter, C. A. J. Biol. Chem. 274, 22123–22126 (1999).

    Article  CAS  Google Scholar 

  11. Deveraux, Q., Ustrell, V., Pickart, C. & Rechsteiner, M. J. Biol. Chem. 269, 7059–7061 (1994).

    CAS  Google Scholar 

  12. Van Nocker, S. et al. Mol. Cell Biol. 11, 6020–6028 (1996).

    Article  Google Scholar 

  13. Fu, H. et al. J. Biol. Chem. 273, 1970–1981 (1998).

    Article  CAS  Google Scholar 

  14. Yen, C.-H. et al. J. Immunol. 165, 6372–6380 (2000).

    Article  CAS  Google Scholar 

  15. Moir, D., Stewart, S. E., Osmond, B. C. & Botstein, D. Genetics 100, 547–563 (1982).

    CAS  Google Scholar 

  16. Ghislain, M., Dohmen, R. J., Levy, F. & Varshavsky, A. EMBO J. 15, 4884–4899 (1996).

    Article  CAS  Google Scholar 

  17. Chen, E. et al. J. Biol. Chem. 273, 35201–35207 (1998).

    Article  CAS  Google Scholar 

  18. Clurman, B. E., Sheaff, R. J., Thress, K., Groudine, M. & Roberts, J. M. Genes Dev. 10, 1979–1990 (1996).

    Article  CAS  Google Scholar 

  19. Won, K. A. & Reed, S. I. EMBO J. 15, 4182–4193 (1996).

    Article  CAS  Google Scholar 

  20. Chau, V. et al. Science 243, 1576–1583 (1989).

    Article  CAS  Google Scholar 

  21. Pickart, C. M. FASEB J. 11, 1055–1066 (1997).

    Article  CAS  Google Scholar 

  22. Thrower, J. S., Hoffman, L., Rechsteiner, M. & Pickart, C. M. EMBO J. 19, 94–102 (2000).

    Article  CAS  Google Scholar 

  23. Young, P., Deveraux, Q., Beal, R. E., Pickart, C. M. & Rechsteiner, M. J. Biol. Chem. 273, 5461–5467 (1998).

    Article  CAS  Google Scholar 

  24. Kondo, H. et al. Nature 388, 75–78 (1997).

    Article  CAS  Google Scholar 

  25. Leon, A. & McKearin, D. Mol. Biol. Cell 10, 3825–3834 (1999).

    Article  CAS  Google Scholar 

  26. Meyer, H. H., Shorter, J. G., Seemann, J., Pappin, D. & Warren, G. EMBO J. 19, 2181–2192 (2000).

    Article  CAS  Google Scholar 

  27. Koegl, M. et al. Cell 96, 635–644 (1999).

    Article  CAS  Google Scholar 

  28. Golbik, R., Lupas, A. N., Koretke, K. K., Baumeister, W. & Peters J. Biol. Chem. 380, 1049–1062 (1999).

    Article  CAS  Google Scholar 

  29. Beckwith, M, Longo, D. L., O' Connell, C. D., Moratz, C. M. & Urba, W. J. J. Natl Cancer Inst. 82, 501–509 (1990).

    Article  CAS  Google Scholar 

  30. Egerton, M. & Samelson L. E. J. Biol. Chem. 269, 11435–11441 (1994).

    CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Intramural Research Support Program, SAIC Frederick, National Cancer Institute at Frederick, Frederick, 21702, Maryland, USA

    Ren Ming Dai & Chou-Chi H. Li

Authors
  1. Ren Ming Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chou-Chi H. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chou-Chi H. Li.

Supplementary information

Supplementary figure

Figure S1Structure-function analyses in multi-Ub chain binding and in vitro Ub-Pr degradation. (PDF 590 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dai, R., Li, CC. Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin–proteasome degradation. Nat Cell Biol 3, 740–744 (2001). https://doi.org/10.1038/35087056

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35087056

  • Springer Nature Limited

This article is cited by

Search

Navigation