1. Institute of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', 34 Alexander Fleming Street, Vari 16672, Greece
2. Cancer Research UK Gene Function & Regulation Group, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK
3. These authors contributed equally to this work

Correspondence to: George Mosialos¹ Email: mosialos@fleming.gr

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-B by specific tumour-necrosis factor receptors (TNFRs). Loss of the deubiquitinating activity of CYLD correlates with tumorigenesis. CYLD inhibits activation of NF-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-B. The inhibition of NF-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-B that is required for appropriate cellular homeostasis of skin appendages.