Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members

Abstract

Familial cylindromatosis is an autosomal dominant predisposition to tumours of skin appendages called cylindromas. Familial cylindromatosis is caused by mutations in a gene encoding the CYLD protein of previously unknown function1. Here we show that CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-κB by specific tumour-necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis. CYLD inhibits activation of NF-κB by the TNFR family members CD40, XEDAR and EDAR in a manner that depends on the deubiquitinating activity of CYLD. Downregulation of CYLD by RNA-mediated interference augments both basal and CD40-mediated activation of NF-κB. The inhibition of NF-κB activation by CYLD is mediated, at least in part, by the deubiquitination and inactivation of TNFR-associated factor 2 (TRAF2) and, to a lesser extent, TRAF6. These results indicate that CYLD is a negative regulator of the cytokine-mediated activation of NF-κB that is required for appropriate cellular homeostasis of skin appendages.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: CYLD is a deubiquitinating enzyme that interacts with NEMO.
Figure 2: Effect of CYLD and truncated forms of CYLD on NF-κB activation by CD40.
Figure 3: Effect of CYLD and CYLD(1–932) on NF-κB activation by TRAF2, TRAF6 and IKKβ.
Figure 4: Effect of CYLD and CYLD(1–932) on TRAF2 and TRAF6 polyubiquitination.

Similar content being viewed by others

References

  1. Bignell, G. R. et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nature Genet. 25, 160–165 (2000)

    Article  CAS  Google Scholar 

  2. Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002)

    Article  CAS  Google Scholar 

  3. Jain, A. et al. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nature Immunol. 2, 223–228 (2001)

    Article  CAS  Google Scholar 

  4. Wilkinson, K. D. Regulation of ubiquitin-dependent processes by deubiquitinating enzymes. FASEB J. 11, 1245–1256 (1997)

    Article  CAS  Google Scholar 

  5. Headon, D. J. & Overbeek, P. A. Involvement of a novel TNF receptor homologue in hair follicle induction. Nature Genet. 22, 370–374 (1999)

    Article  CAS  Google Scholar 

  6. Yan, M. et al. Two-amino acid molecular switch in an epithelial morphogen that regulates binding to two distinct receptors. Science 290, 523–527 (2000)

    Article  ADS  CAS  Google Scholar 

  7. Hatzivassiliou, E. & Mosialos, G. Cellular signaling pathways engaged by the Epstein-Barr virus transforming protein LMP1. Front. Biosci. 7, d319–d329 (2002)

    Article  CAS  Google Scholar 

  8. Nguyen, L. T. et al. TRAF2 deficiency results in hyperactivity of certain TNFR1 signals and impairment of CD40-mediated responses. Immunity 11, 379–389 (1999)

    Article  CAS  Google Scholar 

  9. Lomaga, M. A. et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 13, 1015–1024 (1999)

    Article  CAS  Google Scholar 

  10. Yan, M. et al. Identification of a novel death domain-containing adaptor molecule for ectodysplasin-A receptor that is mutated in crinkled mice. Curr. Biol. 12, 409–413 (2002)

    Article  CAS  Google Scholar 

  11. Naito, A. et al. TRAF6-deficient mice display hypohidrotic ectodermal dysplasia. Proc. Natl Acad. Sci. USA 99, 8766–8771 (2002)

    Article  ADS  CAS  Google Scholar 

  12. Kaye, K. M. et al. Tumor necrosis factor receptor associated factor 2 is a mediator of NF-κB activation by latent infection membrane protein 1, the Epstein–Barr virus transforming protein. Proc. Natl Acad. Sci. USA 93, 11085–11090 (1996)

    Article  ADS  CAS  Google Scholar 

  13. Schultheiss, U. et al. TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1. EMBO J. 20, 5678–5691 (2001)

    Article  CAS  Google Scholar 

  14. Deng, L. et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351–361 (2000)

    Article  CAS  Google Scholar 

  15. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001)

    Article  ADS  CAS  Google Scholar 

  16. Shi, C. S. & Kehrl, J. H. Tumor necrosis factor (TNF)-induced germinal center kinase-related (GCKR) and stress-activated protein kinase (SAPK) activation depends upon the E2/E3 complex Ubc13-Uev1A/TNF receptor-associated factor 2 (TRAF2). J. Biol. Chem. 278, 15429–15434 (2003)

    Article  CAS  Google Scholar 

  17. McKenna, S. et al. An NMR-based model of the ubiquitin-bound human ubiquitin conjugation complex Mms2-Ubc13. The structural basis for lysine 63 chain catalysis. J. Biol. Chem. 278, 13151–13158 (2003)

    Article  CAS  Google Scholar 

  18. Devin, A. et al. The distinct roles of TRAF2 and RIP in IKK activation by TNF-R1: TRAF2 recruits IKK to TNF-R1 while RIP mediates IKK activation. Immunity 12, 419–429 (2000)

    Article  CAS  Google Scholar 

  19. Devin, A. et al. The α and β subunits of IκB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor necrosis factor (TNF) receptor 1 in response to TNF. Mol. Cell. Biol. 21, 3986–3994 (2001)

    Article  CAS  Google Scholar 

  20. Zhang, S. Q., Kovalenko, A., Cantarella, G. & Wallach, D. Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKγ) upon receptor stimulation. Immunity 12, 301–311 (2000)

    Article  CAS  Google Scholar 

  21. Hu, M. et al. Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell 111, 1041–1054 (2002)

    Article  CAS  Google Scholar 

  22. Karin, M., Cao, Y., Greten, F. R. & Li, Z. W. NF-κB in cancer: from innocent bystander to major culprit. Nature Rev. Cancer 2, 301–310 (2002)

    Article  CAS  Google Scholar 

  23. Brummelkamp, T. R., Nijman, S. M. B., Dirac, A. M. G. & Bernards, R. Loss of cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. Nature 424, 797–801 (2003)

    Article  ADS  CAS  Google Scholar 

  24. Mosialos, G. et al. The Epstein–Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80, 389–399 (1995)

    Article  CAS  Google Scholar 

  25. Mitchell, T. & Sugden, B. Stimulation of NF-κB-mediated transcription by mutant derivatives of the latent membrane protein of Epstein–Barr virus. J. Virol. 69, 2968–2976 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Hatzivassiliou, E., Cardot, P., Zannis, V. I. & Mitsialis, S. A. Ultraspiracle, a Drosophila retinoic X receptor α homologue, can mobilize the human thyroid hormone receptor to transactivate a human promoter. Biochemistry 36, 9221–9231 (1997)

    Article  CAS  Google Scholar 

  27. Devergne, O. et al. Association of TRAF1, TRAF2, and TRAF3 with an Epstein–Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF- κB activation. Mol. Cell. Biol. 16, 7098–7108 (1996)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. D'Andrea, Z. J. Chen, C. H. Chung, V. Dixit, M. Hochstrasser, E. Kieff, H. Kikutani, B. Lim, A. Koromilas, H. Nakano, M. Oren and S. Tronick for reagents; and D. Thanos and G. Panayotou for critically reading the manuscript. This work was supported by an International Scholarship from the Howard Hughes Medical Institute, a Human Frontiers Science Program grant and an EMBO Young Investigator award to G.M., and by Cancer Research UK funding to A.A.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to George Mosialos.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trompouki, E., Hatzivassiliou, E., Tsichritzis, T. et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members. Nature 424, 793–796 (2003). https://doi.org/10.1038/nature01803

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01803

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing