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CYLD Is a Deubiquitinating Enzyme That Negatively Regulates NF-Kb

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CYLD Is a Deubiquitinating Enzyme That Negatively Regulates NF-Kb letters to nature 13. Schwartz, S. et al. Human–mouse alignments with BLASTZ. Genome Res 13, 103–107 (2003). necrosis factor receptors (TNFRs). Loss of the deubiquitinating 14. Schwartz, S. et al. MultiPipMaker and supporting tools: alignments and analysis of multiple genomic activity of CYLD correlates with tumorigenesis. CYLD inhibits DNA sequences. Nucleic Acids Res. 31, 3518–3524 (2003). 15.Murphy,W.J.et al. Resolution of the early placental mammal radiation using Bayesian phylogenetics. activation of NF-kB by the TNFR family members CD40, XEDAR Science 294, 2348–2351 (2001). and EDAR in a manner that depends on the deubiquitinating 16. Poux, C., Van Rheede, T., Madsen, O. & de Jong, W. W. Sequence gaps join mice and men: activity of CYLD. Downregulation of CYLD by RNA-mediated phylogenetic evidence from deletions in two proteins. Mol. Biol. Evol. 19, 2035–2037 (2002). 17. Huelsenbeck, J. P., Larget, B. & Swofford, D. A compound Poisson process for relaxing the molecular interference augments both basal and CD40-mediated activation clock. Genetics 154, 1879–1892 (2000). of NF-kB. The inhibition of NF-kBactivationbyCYLDis 18. Cooper, G. M. et al. Quantitative estimates of sequence divergence for comparative analyses of mediated, at least in part, by the deubiquitination and inacti- mammalian genomes. Genome Res. 13, 813–820 (2003). vation of TNFR-associated factor 2 (TRAF2) and, to a lesser 19. Siepel, A. & Haussler, D. Proc. 7th Annual Int. Conf. Research in Computational Molecular Biology (ACM, New York, 2003). extent, TRAF6. These results indicate that CYLD is a negative 20. Hardison, R. C. et al. Covariation in frequencies of substitution, deletion, transposition, and regulator of the cytokine-mediated activation of NF-kB that is recombination during eutherian evolution. Genome Res. 13, 13–26 (2003). required for appropriate cellular homeostasis of skin 21. Green, P. et al. Transcription-associated mutational asymmetry in mammalian evolution. Nature appendages. Genet. 33, 514–517 (2003). 22. Frazer, K. A. et al. Genomic DNA insertions and deletions occur frequently between humans and Activation of NF-kB by cytokines depends on the activity of the nonhuman primates. Genome Res. 13, 341–346 (2003). IkB kinase (IKK) complex, which mediates phosphorylation of the 23. Britten, R. J. Divergence between samples of chimpanzee and human DNA sequences is 5%, counting NF-kB inhibitor IkB2. NEMO (also known as IKK-g) is an essential indels. Proc. Natl Acad. Sci. USA 99, 13633–13635 (2002). component of the IKK complex. IKK-mediated phosphorylation of 24. Springer, M. S., Murphy, W. J., Eizirik, E. & O’Brien, S. J. Placental mammal diversification and the Cretaceous/Tertiary boundary. Proc. Natl Acad. Sci. USA 100, 1056–1061 (2003). IkB causes its degradation by the ubiquitin–proteasome pathway 25. Li, W. H., Ellsworth, D. L., Krushkal, J., Chang, B. H. & Hewett-Emmett, D. Rates of nucleotide and results in nuclear translocation and activation of NF-kB. substitution in primates and rodents and the generation-time effect hypothesis. Mol. Phylogenet. Evol. A yeast two-hybrid screen with NEMO as the bait identified 5, 182–187 (1996). complementary DNAs encoding either the alternatively spliced, 26. Kumar, S. & Subramanian, S. Mutation rates in mammalian genomes. Proc. Natl Acad. Sci. USA 99, 803–808 (2002). ‘full-length’ CYLD of 953 amino acids or two truncated forms of 27. Shizuya, H. et al. Cloning and stable maintenance of 300-kilobase-pair fragments of human DNA in the protein spanning amino acids 211–709 and 387–953. The Escherichia coli using an F-factor-based vector. Proc. Natl Acad. Sci. USA 89, 8794–8797 (1992). interaction of CYLD with NEMO was specific, because full-length 28. Thomas, J. W. et al. Parallel construction of orthologous sequence-ready clone contig maps in CYLD did not interact with two mutated forms of NEMO (C417R multiple species. Genome Res. 12, 1277–1285 (2002). 29. Burge, C. & Karlin, S. Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. and D406V) that have an altered carboxy-terminal zinc-finger 3 268, 78–94 (1997). motif . Todetermine whether this association occurs in mammalian 30. Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002). cells, Flag-tagged CYLD and glutathione S-transferase (GST)- tagged NEMO were coexpressed in human embryonic kidney Supplementary Information accompanies the paper on www.nature.com/nature. (HEK) 293T cells. Co-precipitation experiments indicated that Acknowledgements We thank J. Weissenbach and H. Roest Crollius for Tetraodon BACs; CYLD and NEMO can indeed interact in mammalian cells after M. Diekhans for computational expertise; N. Goldman and Z. Yang for advice on phylogenetic their coexpression (Fig. 1a, b). The amino-terminal region of CYLD analyses; and F. Collins and J. Mullikin for critically reading the manuscript. We acknowledge the mediates the interaction with NEMO, because deletion of the support of the National Human Genome Research Institute (National Institutes of Health) and the Howard Hughes Medical Institute. N-terminal 537 amino acids of CYLD abolished NEMO binding (Fig. 1c). We could not detect an interaction between endogenous Competing interests statement The authors declare that they have no competing financial CYLD and NEMO, either because of the possible transient nature interests. of this interaction or because of the relatively low affinity of our antisera against CYLD. Correspondence and requests for materials should be addressed to E.D.G. The C-terminal 365 amino acids of CYLD contain motifs found ([email protected]). GenBank accession numbers for BAC-derived sequences are provided in the Supplementary Information. in ubiquitin-specific proteases (UBPs), a subclass of deubiquitinat- ing enzymes thought to be responsible for the removal of poly- ubiquitin chains from polypeptides1,4. Most pathogenic inactivating mutations of CYLD result in truncations or frameshift alterations of the C-terminal region of the molecule1. To determine whether .............................................................. CYLD can act as a UBP, Flag-tagged wild-type CYLD and three C-terminally truncated mutants of CYLD that are associated CYLD is a deubiquitinating enzyme with familial cylindromatosis (encoding residues 1–932, 1–864 and 1–754 of CYLD; see Online Mendelian Inheritance in Man that negatively regulates NF-kB number 132700 at http://ncbi.nlm.gov/Omim/) were expressed in activation by TNFR family members HEK 293T cells, immunoprecipitated and tested for their ability to cleave tetraubiquitin. Wild-type CYLD readily cleaved the tetra- meric substrate to its monomer, dimer and trimer; however, the Eirini Trompouki1, Eudoxia Hatzivassiliou1*, Theodore Tsichritzis1*, Hannah Farmer2, Alan Ashworth2 & George Mosialos1 pathogenic mutations associated with familial cylindromatosis abolished the UBP activity of CYLD, indicating a correlation 1Institute of Immunology, Biomedical Sciences Research Center ‘Alexander between tumorigenesis and loss of the deubiquitinating activity of Fleming’, 34 Alexander Fleming Street, Vari 16672, Greece CYLD (Fig. 1d, top). The deubiquitinating activity of CYLD did not 2Cancer Research UK Gene Function & Regulation Group, The Breakthrough require any other mammalian proteins, because it was detectable in Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty bacteria (Supplementary Fig. 1). In addition, the deubiquitinating Laboratories, 237 Fulham Road, London SW3 6JB, UK activity of CYLD was abolished by replacing the conserved catalytic * These authors contributed equally to this work residue Cys 601 with serine. ............................................................................................................................................................................. The interaction of CYLD with NEMO prompted us to investigate Familial cylindromatosis is an autosomal dominant predisposi- the potential involvement of CYLD in NF-kB activation. CD40, tion to tumours of skin appendages called cylindromas. Familial XEDAR and EDAR are members of the TNFR family implicated cylindromatosis is caused by mutations in a gene encoding the in the proper development of skin appendages from which cylin- CYLD protein of previously unknown function1. Here we show dromas arise3,5,6. Expression of wild-type CYLD in HEK 293T cells that CYLD is a deubiquitinating enzyme that negatively regulates inhibited the ability of coexpressed CD40 (Fig. 2a), XEDAR or activation of the transcription factor NF-kB by specific tumour- EDAR (Supplementary Fig. 2) to activate the NF-kB pathway; by NATURE | VOL 424 | 14 AUGUST 2003 | www.nature.com/nature © 2003 Nature Publishing Group 793 letters to nature contrast, the CYLD mutant associated with familial cylindromatosis mediated NF-kB activation by CYLD, we studied the point in the that lacks 21 amino acids at its C terminus was markedly impaired signalling pathway at which CYLD interferes. TRAF2 and TRAF6 in its ability to inhibit NF-kB activation by these receptors. have been implicated in the activation of NF-kB by CD40, EDAR, CYLD(538–953), which is catalytically active but does not bind to XEDAR and LMP1 (refs 6, 8–13). TRAF2 and TRAF6 interact NEMO, also failed to inhibit CD40-mediated activation of NF-kB, directly or indirectly with the cytoplasmic tail of the receptor. suggesting that the NF-kB inhibitory activity of CYLD is dependent These proteins are activated by oligomerization, and this event on NEMO (Fig.
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