XIAP Induces NF-κB Activation via the BIR1/TAB1 Interaction and BIR1 Dimerization

Miao Lu, Su Chang Lin, Yihua Huang, Young Jun Kang, Rebecca Rich, Yu Chih Lo, David Myszka, Jiahuai Han, Hao Wu

Research output: Contribution to journalArticlepeer-review

199 Citations (Scopus)

Abstract

In addition to caspase inhibition, X-linked inhibitor of apoptosis (XIAP) induces NF-κB 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-κB activation. TAB1 is an upstream adaptor for the activation of the kinase TAK1, which in turn couples to the NF-κB 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-κB 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-κB activation, implicating a proximity-induced mechanism for TAK1 activation.

Original languageEnglish
Pages (from-to)689-702
Number of pages14
JournalMolecular Cell
Volume26
Issue number5
DOIs
Publication statusPublished - 2007 Jun 8

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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