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., Davis, C. A. , Shimizu, A., Escors, D., Bagnéris, C., Barrett, T. 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(14), pp. 7608-7620. (doi: 10.1074/jbc.M116.718122) (PMID:26865630) (PMCID:PMC4817188)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Davis, Dr Chris
• Authors: Baratchian, M., Davis, C. A., Shimizu, A., Escors, D., Bagnéris, C., Barrett, T., and Collins, M. K.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Biological Chemistry
• Publisher: American Society for Biochemistry and Molecular Biology, Inc.
• ISSN: 0021-9258
• ISSN (Online): 1083-351X
• Published Online: 10 February 2016
• Copyright Holders: Copyright © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
• First Published: First published in Journal of Biological Chemistry 291(14):7608-7620
• Publisher Policy: Reproduced under a Creative Commons licence