Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB

Abstract

Protein modification by the conjugation of ubiquitin moieties—ubiquitination—plays a major part in many biological processes, including cell cycle and apoptosis1. The enzymes that mediate ubiquitin-conjugation have been well-studied, but much less is known about the ubiquitin-specific proteases that mediate de-ubiquitination of cellular substrates2,3. To study this gene family, we designed a collection of RNA interference vectors to suppress 50 human de-ubiquitinating enzymes, and used these vectors to identify de-ubiquitinating enzymes in cancer-relevant pathways. We report here that inhibition of one of these enzymes, the familial cylindromatosis tumour suppressor gene (CYLD)4, having no known function, enhances activation of the transcription factor NF-κB. We show that CYLD binds to the NEMO (also known as IKKγ) component of the IκB kinase (IKK) complex, and appears to regulate its activity through de-ubiquitination of TRAF2, as TRAF2 ubiquitination can be modulated by CYLD. Inhibition of CYLD increases resistance to apoptosis, suggesting a mechanism through which loss of CYLD contributes to oncogenesis. We show that this effect can be relieved by aspirin derivatives that inhibit NF-κB activity5, which suggests a therapeutic intervention strategy to restore growth control in patients suffering from familial cylindromatosis.

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Figure 1: Genome-wide DUB knockdown screen.
Figure 2: CYLD is an antagonist of NF-κB signalling.
Figure 3: CYLD loss protects against TNF-α induced apoptosis.
Figure 4: Anti-apoptotic effects of CYLD loss can be reversed by aspirin.

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Acknowledgements

We thank S. Lens, A. Lund and J. Borst for reagents, and M. Madiredjo for assistance. This work was supported by the Centre for Biomedical Genetics (CBG) and the Netherlands Organization for Scientific Research (NWO). A.D. was supported by a long-term fellowship from EMBO.

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Correspondence to René Bernards.

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Brummelkamp, T., Nijman, S., Dirac, A. et al. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. Nature 424, 797–801 (2003). https://doi.org/10.1038/nature01811

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