title: 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).
abstract: The viral FLICE-like inhibitory protein (FLIP) protein from Kaposi sarcoma-associated herpesvirus activates the NF-κB pathway by forming a stable complex with a central region (amino acids 150-272) of the inhibitor of NF-κB kinase (IKK) γ subunits, thereby activating IKK. Cellular FLIP (cFLIP) forms are also known to activate the NF-κB pathway via IKK activation. Here we demonstrate that cFLIPL, cFLIPS, and their proteolytic product p22-FLIP all require the C-terminal region of NEMO/IKKγ (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 IKKγ. Our results further reveal that cFLIPLrequires the linear ubiquitin chain assembly complex and the kinase TAK1 for activation of the IKK kinase. Similarly, cFLIPSand p22-FLIP also require TAK1 but do not require LUBAC. In contrast, these isoforms are both components of complexes that incorporate Fas-associated death domain 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.
authors: From the Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom, Division of Advanced Therapies, National Institute of Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Herts EN6 3QG, United Kingdom, and.
authors: Mehdi
authors: M
authors: Baratchian
authors: From the Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom.
authors: Christopher A
authors: CA
authors: Davis
authors: From the Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom.
authors: Akira
authors: A
authors: Shimizu
authors: From the Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom.
authors: David
authors: D
authors: Escors
authors: Institute of Structural and Molecular Biology, School of Biological Sciences, Birkbeck College, Malet Street, London WC1E 7HX, United Kingdom.
authors: Claire
authors: C
authors: Bagnéris
authors: Institute of Structural and Molecular Biology, School of Biological Sciences, Birkbeck College, Malet Street, London WC1E 7HX, United Kingdom.
authors: Tracey
authors: T
authors: Barrett
authors: From the Medical Research Council Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom, Division of Advanced Therapies, National Institute of Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Herts EN6 3QG, United Kingdom, and mary.collins@ucl.ac.uk.
authors: Mary K
authors: MK
authors: Collins
mesh_terms: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D025801:Ubiquitin; D000099151:MAP Kinase Kinase Kinase 7; C119724:AGFG1 protein, human
keywords: NF-κB; cell signaling; death domain; protein kinase; ubiquitylation (ubiquitination)