CYLD is a deubiquitinating enzyme that negatively regulates NF-[kappa]B activation by TNFR family members.
Trompouki, Eirini 1; Hatzivassiliou, Eudoxia 1*; Tsichritzis, Theodore 1*; Farmer, Hannah 2; Ashworth, Alan 2; Mosialos, George 1
[Letter] Nature. 424(6950):793-796, August 14, 2003.

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

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