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    Distinct activation mechanisms of NF-κB regulator inhibitor of NF-κB Kinase (IKK) by isoforms of the Cell Death Regulator Cellular FLICE-like Inhibitory Protein (cFLIP)*

    Baratchian, M. and Davis, C.A. and Shimizu, A. and Escors, D. and Bagneris, Claire and Barrett, Tracey E. and Collins, M.K. (2016) Distinct activation mechanisms of NF-κB regulator inhibitor of NF-κB Kinase (IKK) by isoforms of the Cell Death Regulator Cellular FLICE-like Inhibitory Protein (cFLIP)*. Journal of Biological Chemistry 291 , pp. 7608-7620. ISSN 0021-9258.

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    Abstract

    The vFLIP protein from Kaposis sarcoma-associated herpesvirus activates the NF-kB pathway by forming a stable complex with a central region (amino acids 150-272) of the IKKgamma subunit, thereby activating IKK. Cellular FLIP forms are also known to activate the NF-kB pathway via IKK activation. Here we demonstrate that cFLIPL, cFLIPS, and their proteolytic product p22-FLIP, all require the C-terminal region of NEMO/IKKgamma (amino acids 272-419) and its ubiquitin binding function for activation of the IKK kinase (or kinase complex), but none form a stable complex with IKKgamma. Our results further reveal that cFLIPL requires the linear ubiquitination complex LUBAC and the kinase TAK1 for activation of the IKK kinase. Similarly, cFLIPS and p22-FLIP also require TAK1 but do not require LUBAC. In contrast, these isoforms are both components of complexes that incorporate FADD and RIP1 which appear essential for kinase activation. This conservation of IKK activation among the cFLIP family using different mechanisms suggests that the mechanism plays a critical role in their function.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): cell signaling, death domain, NF-kappa B (NF-KB) protein kinase, ubiquitylation (ubiquitination)
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 01 Mar 2016 13:14
    Last Modified: 09 Feb 2017 06:52
    URI: http://eprints.bbk.ac.uk/id/eprint/14534

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