CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members.
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 function. Here we show that CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-kappaB by specific tumour-necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis. CYLD inhibits activation of NF-kappaB 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-kappaB. The inhibition of NF-kappaB 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-kappaB that is required for appropriate cellular homeostasis of skin appendages.
Trompouki
Eirini
E
Institute of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', 34 Alexander Fleming Street, Vari 16672, Greece.
Hatzivassiliou
Eudoxia
E
Tsichritzis
Theodore
T
Farmer
Hannah
H
Ashworth
Alan
A
Mosialos
George
G
D019013:CD40 Antigens / Q000378:metabolism; D002460:Cell Line; D000074749:Deubiquitinating Enzyme CYLD; D053339:Edar Receptor; D006801:Humans; D051550:I-kappa B Kinase; D008565:Membrane Proteins / Q000378:metabolism; 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; D034622:RNA Interference; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D053340:Xedar Receptor
D019013:CD40 Antigens; C506011:EDA2R protein, human; C506008:EDAR protein, human; D053339:Edar Receptor; D008565:Membrane Proteins; D016328:NF-kappa B; D011506:Proteins; D053338:Receptors, Ectodysplasin; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D053340:Xedar Receptor; 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