XIAP Induces NF-kB Activation via the BIR1/TAB1 Interaction and BIR1 Dimerization
In addition to caspase inhibition, X-linked inhibitor of apoptosis (XIAP) induces NF-{kappa}B and MAP kinase activation during TGF-b and BMP receptor signaling and upon overexpression. Here we show that the BIR1 domain of XIAP, which has no previously ascribed function, directly interacts with TAB1 to induce NF-{kappa}B activation. TAB1 is an upstream adaptor for the activation of the kinase TAK1, which in turn couples to the NF-{kappa}B pathway. We report the crystal structures of BIR1, TAB1, and the BIR1/TAB1 complex. The BIR1/TAB1 structure reveals a striking butterfly-shaped dimer and the detailed interaction between BIR1 and TAB1. Structure-based mutagenesis and knockdown of TAB1 show unambiguously that the BIR1/TAB1 interaction is crucial for XIAP-induced TAK1 and NF-{kappa}B activation. We show that although not interacting with BIR1, Smac, the antagonist for caspase inhibition by XIAP, also inhibits the XIAP/TAB1 interaction. Disruption of BIR1 dimerization abolishes XIAP-mediated NF-{kappa}B activation, implicating a proximity-induced mechanism for TAK1 activation.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
- Sponsoring Organization:
- Doe - Office Of Science
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 930470
- Report Number(s):
- BNL-81222-2008-JA; TRN: US200904%%737
- Journal Information:
- Molecular Cell, Vol. 26, Issue 5; ISSN 1097-2765
- Country of Publication:
- United States
- Language:
- English
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