CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members

Eirini Trompouki, Eudoxia Hatzivassiliou, Theodore Tsichritzis, Hannah Farmer, Alan Ashworth and George Mosialos ()
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Eirini Trompouki: Biomedical Sciences Research Center ‘Alexander Fleming’
Eudoxia Hatzivassiliou: Biomedical Sciences Research Center ‘Alexander Fleming’
Theodore Tsichritzis: Biomedical Sciences Research Center ‘Alexander Fleming’
Hannah Farmer: Institute of Cancer Research, Chester Beatty Laboratories
Alan Ashworth: Institute of Cancer Research, Chester Beatty Laboratories
George Mosialos: Biomedical Sciences Research Center ‘Alexander Fleming’

Nature, 2003, vol. 424, issue 6950, 793-796

Abstract: Abstract 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 function1. Here we show that CYLD is a deubiquitinating enzyme that negatively regulates activation of the transcription factor NF-κB by specific tumour-necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis. CYLD inhibits activation of NF-κB 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-κB. The inhibition of NF-κB 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-κB that is required for appropriate cellular homeostasis of skin appendages.

Date: 2003
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DOI: 10.1038/nature01803

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