Activation of NF-κB by XIAP, the X chromosome-linked inhibitor of apoptosis, in endothelial cells involves TAK1

Exposure of endothelial and many other cell types to tumor necrosis factor α generates both apoptotic and anti-apoptotic signals. The anti-apoptotic pathway leads to activation of the transcription factor NF-κB that regulates the expression of genes such as A20 or members of the IAP gene family that protect cells from tumor necrosis factor α-mediated apoptosis. In turn, some anti-apoptotic genes have been shown to modulate NF-κB activity. Here we demonstrate that XIAP, a NF-κB-dependent member of the IAP gene family, is a strong stimulator of NF-κB. Expression of XIAP leads to increased nuclear translocation of the p65 subunit of NF-κB via a novel signaling pathway that involves the mitogen-activated protein kinase kinase kinase TAK1. We show that TAK1 physically interacts with NIK and with IKK2, and both XIAP or active TAK1 can stimulate IKK2 kinase activity. Thus, XIAP may be part of a system of regulatory loops that balance a cell's response to environmental stimuli.