XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization.
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.
Lu
Miao
M
Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021, USA.
Lin
Su-Chang
SC
Huang
Yihua
Y
Kang
Young Jun
YJ
Rich
Rebecca
R
Lo
Yu-Chih
YC
Myszka
David
D
Han
Jiahuai
J
Wu
Hao
H
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D020349:Surface Plasmon Resonance; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; C099510:TAB1 protein, MAPKKK activator, vertebrate; C486300:TAB1 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human