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

Mol Cell. 2007 Jun 8;26(5):689-702. doi: 10.1016/j.molcel.2007.05.006.

Abstract

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

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins
  • Cell Line
  • Cells, Cultured
  • Crystallography, X-Ray
  • Dimerization
  • Humans
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mitochondrial Proteins / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Static Electricity
  • Surface Plasmon Resonance
  • X-Linked Inhibitor of Apoptosis Protein / chemistry*
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Multiprotein Complexes
  • NF-kappa B
  • Recombinant Fusion Proteins
  • TAB1 protein, MAPKKK activator, vertebrate
  • TAB1 protein, human
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human