title: XIAP regulates bi-phasic NF-kappaB induction involving physical interaction and ubiquitination of MEKK2.
abstract: The transcription factor NF-kappaB 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-kappaB activity, however, the underlying molecular mechanism has remained elusive. We show here that following TNFalpha stimulation XIAP regulates a second wave of NF-kappaB activation. XIAP interacts with and ubiquitinates MEKK2, a kinase that has previously been associated with bi-phasic NF-kappaB activation. We conclude that, through interaction with MEKK2, XIAP functions in an ubiquitin ligase dependent manner to evoke a second wave of NF-kappaB activation, resulting in the modulation of NF-kappaB target gene expression.
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Winsauer
authors.forename: Ulrike
authors.initials: U
authors.lastname: Resch
authors.forename: Renate
authors.initials: R
authors.lastname: Hofer-Warbinek
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Schichl
authors.forename: Rainer
authors.initials: R
authors.lastname: de Martin