The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes.
The CARD domain protein BCL10 and paracaspase MALT1 are essential for the activation of IkappaB kinase (IKK) and NF-kappaB in response to T cell receptor (TCR) stimulation. Here we present evidence that TRAF6 ubiquitin ligase and TAK1 protein kinase mediate IKK activation by BCL10 and MALT1. RNAi-mediated silencing of MALT1, TAK1, TRAF6, and TRAF2 suppressed TCR-dependent IKK activation and interleukin-2 production in T cells. Furthermore, we have reconstituted the pathway from BCL10 to IKK activation in vitro with purified proteins of MALT1, TRAF6, TAK1, and ubiquitination enzymes including Ubc13/Uev1A. We find that a small fraction of BCL10 and MALT1 proteins form high molecular weight oligomers. Strikingly, only these oligomeric forms of BCL10 and MALT1 can activate IKK in vitro. The MALT1 oligomers bind to TRAF6, induce TRAF6 oligomerization, and activate the ligase activity of TRAF6 to polyubiquitinate NEMO. These results reveal an oligomerization --> ubiquitination --> phosphorylation cascade that culminates in NF-kappaB activation in T lymphocytes.
Sun
Lijun
L
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Deng
Li
L
Ea
Chee-Kwee
CK
Xia
Zong-Ping
ZP
Chen
Zhijian J
ZJ
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D007113:Immunity, Innate / Q000502:physiology; D007376:Interleukin-2 / Q000378:metabolism; D018442:Lymphoma, B-Cell, Marginal Zone; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D046911:Macromolecular Substances; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D002352:Carrier Proteins; D020169:Caspases; D051550:I-kappa B Kinase; D007376:Interleukin-2; D020930:MAP Kinase Kinase Kinases; D046911:Macromolecular Substances; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors; D025801:Ubiquitin; D044763:Ubiquitin-Conjugating Enzymes; D000099151:MAP Kinase Kinase Kinase 7; C118591:BCL10 protein, human; C471624:UBE2V1 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C400109:MALT1 protein, human