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Distinct Activation Mechanisms of NF-?B Regulator Inhibitor of NF-?B 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-?B pathway by forming a stable complex with a central region (amino acids 150-272) of the inhibitor of NF-?B kinase (IKK) ? subunits, thereby activating IKK. Cellular FLIP (cFLIP) forms are also known to activate the NF-?B pathway via IKK activation. Here we demonstrate that cFLIPL, cFLIPS, and their proteolytic product p22-FLIP all require the C-terminal region of NEMO/IKK? (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 IKK?. 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.

SUBMITTER: Baratchian M 

PROVIDER: S-EPMC4817188 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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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 Mehdi M   Davis Christopher A CA   Shimizu Akira A   Escors David D   Bagnéris Claire C   Barrett Tracey T   Collins Mary K MK  

The Journal of biological chemistry 20160210 14


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  ...[more]

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