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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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’.
The authors declare that they have no competing financial interests.
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European Journal of Neuroscience (2019)
C-Cbl negatively regulates TRAF6-mediated NF-κB activation by promoting K48-linked polyubiquitination of TRAF6
Cellular & Molecular Biology Letters (2019)
Nature Reviews Molecular Cell Biology (2019)
Cellular Immunology (2019)
International Immunology (2019)