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

The transcription factor NF-κB is transiently activated by a wide variety of stress signals, including pro-inflammatory mediators, and regulates the expression of genes with e.g., immune, inflammatory, and anti-apoptotic 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-κB activity, however, the underlying molecular mechanism has remained elusive. We show here that following TNFα stimulation XIAP regulates a second wave of NF-κB activation. XIAP interacts with and ubiquitinates MEKK2, a kinase that has previously been associated with bi-phasic NF-κB activation. We conclude that, through interaction with MEKK2, XIAP functions in an ubiquitin ligase dependent manner to evoke a second wave of NF-κB activation, resulting in the modulation of NF-κB target gene expression.