XIAP regulates bi-phasic NF-κB induction involving physical interaction and ubiquitination of MEKK2

The transcription factor NF-kappa B is transiently activated by a wide variety of stress signals, including proinflammatory mediators, and regulates the expression of genes with e.g., immune, inflammatory, and antiapoptotic functions. The strength and kinetics of its induction, as well as its ultimate down-regulation is subject to multiple levels of regulation. One Such regulatory protein is X chromosome-linked inhibitor Of apoptosis (XIAP) that, besides its anti-apoptotic properties, has been shown to enhance NF-kappa B activity, however, the underlying molecular mechanism has remained elusive. We show here that following TNF alpha stimulation XIAP regulates a second wave of NF-kappa B activation. XIAP interacts with and ubiquitinates MEKK2, a kinase that has previously been associated with bi-phasic NF-kappa B activation. We conclude that, through interaction with MEKK2, XIAP functions in an ubiquitin ligase dependent manner to evoke a second wave of NF-kappa B activation, resulting in the modulation of NF-kappa B target gene expression. (c) 2008 Elsevier Inc. All rights reserved