The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination.
NF-kappaB transcription factors have key roles in inflammation, immune response, oncogenesis and protection against apoptosis. In most cells, these factors are kept inactive in the cytoplasm through association with IkappaB inhibitors. After stimulation by various reagents, IkappaB is phosphorylated by the IkappaB kinase (IKK) complex and degraded by the proteasome, allowing NF-kappaB to translocate to the nucleus and activate its target genes. Here we report that CYLD, a tumour suppressor that is mutated in familial cylindromatosis, interacts with NEMO, the regulatory subunit of IKK. 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.
Kovalenko
Andrew
A
Department of Biological Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel.
Chable-Bessia
Christine
C
Cantarella
Giuseppina
G
Israël
Alain
A
Wallach
David
D
Courtois
Gilles
G
D000595:Amino Acid Sequence; D002384:Catalysis; D002460:Cell Line; D000074749:Deubiquitinating Enzyme CYLD; D006801:Humans; D051550:I-kappa B Kinase; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D047992:TNF Receptor-Associated Factor 2; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D016328:NF-kappa B; D011506:Proteins; D034741:RNA, Small Interfering; D047992:TNF Receptor-Associated Factor 2; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD