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

• Published in: Cellular signalling Vol. 20; no. 11; p. 2107
• Main Authors: Winsauer, Gabriele, Resch, Ulrike, Hofer-Warbinek, Renate, Schichl, Yvonne M, de Martin, Rainer
• Format: Journal Article
• Language: English
• Published: England 01.11.2008
• Subjects: Animals; Cell Line; Cell Nucleus - metabolism; Gene Expression Regulation; Humans; Kinetics; Macrophages - metabolism; MAP Kinase Kinase Kinases - metabolism; Mice; NF-kappa B - metabolism; Protein Binding; Protein Transport; Ubiquitination; X-Linked Inhibitor of Apoptosis Protein - metabolism
• ISSN: 0898-6568
• DOI: 10.1016/j.cellsig.2008.08.004

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.