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.
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Acknowledgements
We thank A. D'Andrea, Z. J. Chen, C. H. Chung, V. Dixit, M. Hochstrasser, E. Kieff, H. Kikutani, B. Lim, A. Koromilas, H. Nakano, M. Oren and S. Tronick for reagents; and D. Thanos and G. Panayotou for critically reading the manuscript. This work was supported by an International Scholarship from the Howard Hughes Medical Institute, a Human Frontiers Science Program grant and an EMBO Young Investigator award to G.M., and by Cancer Research UK funding to A.A.
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Trompouki, E., Hatzivassiliou, E., Tsichritzis, T. et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by TNFR family members. Nature 424, 793–796 (2003). https://doi.org/10.1038/nature01803
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DOI: https://doi.org/10.1038/nature01803
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