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

Andrew Kovalenko, Christine Chable-Bessia, Giuseppina Cantarella, Alain Israël, David Wallach () and Gilles Courtois
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Andrew Kovalenko: The Weizmann Institute of Science
Christine Chable-Bessia: CNRS URA 2582, Institut Pasteur
Giuseppina Cantarella: The Weizmann Institute of Science
Alain Israël: CNRS URA 2582, Institut Pasteur
David Wallach: The Weizmann Institute of Science
Gilles Courtois: CNRS URA 2582, Institut Pasteur

Nature, 2003, vol. 424, issue 6950, 801-805

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01802

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