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The tumour suppressor CYLD negatively regulates NF-κB signalling by deubiquitination

Abstract

NF-κB transcription factors have key roles in inflammation, immune response, oncogenesis and protection against apoptosis1,2. In most cells, these factors are kept inactive in the cytoplasm through association with IκB inhibitors. After stimulation by various reagents, IκB is phosphorylated by the IκB kinase (IKK) complex3 and degraded by the proteasome, allowing NF-κB to translocate to the nucleus and activate its target genes. Here we report that CYLD, a tumour suppressor that is mutated in familial cylindromatosis4, interacts with NEMO, the regulatory subunit of IKK5,6. CYLD also interacts directly with tumour-necrosis factor receptor (TNFR)-associated factor 2 (TRAF2), an adaptor molecule involved in signalling by members of the family of TNF/nerve growth factor receptors. CYLD has deubiquitinating activity that is directed towards non-K48-linked polyubiquitin chains, and negatively modulates TRAF-mediated activation of IKK, strengthening the notion that ubiquitination is involved in IKK activation by TRAFs and suggesting that CYLD functions in this process. Truncations of CYLD found in cylindromatosis result in reduced enzymatic activity, indicating a link between impaired deubiquitination of CYLD substrates and human pathophysiology.

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Acknowledgements

We thank R. Agami for the pSUPER vector and advice; R. Beyaert, C. J. Kirschning, M. Krönke, F. Mercurio, K.-I. Nakayama, M. Rowe and M. Treier for plasmids; T. Goncharov, S. Leu, D. Landstein, M. Pasparakis, F. Agou and S. Yamaoka for discussions and support; and I. Beilis and T. Lopez for technical assistance. This work was supported in part by grants from Inter-Lab Ltd, from Ares Trading SA and from the Alfred and Ann Goldstein Foundation to A.K., G.Ca amd D.W., from PTR Pasteur/Necker to G.Co, and from ‘La ligue Nationale contre le Cancer’ (équipe labellisée) to A.I. A.K. was supported by a postdoctoral fellowship from ‘La ligue Nationale contre le Cancer’.

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Correspondence to David Wallach.

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The authors declare that they have no competing financial interests.

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Further reading

Figure 1: Mapping the binding of CYLD to NEMO and TRAF2 in yeast.
Figure 2: In vivo interaction of CYLD with NEMO and TRAF2.
Figure 3: CYLD is an active UBP deubiquitinase with restricted substrate specificity.
Figure 4: Overexpression of CYLD inhibits NF-κB activation and this inhibition requires its catalytic activity.
Figure 5: CYLD is a negative regulator of the TRAF2 and NF-κB signalling pathway.

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