NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation.
The mechanism by which the Carma1-Bcl10-MALT1 (CBM) complex couples T cell antigen receptor (TCR) signaling to IkappaB kinase (IKK) and NF-kappaB activation is not known. Here, we show that Bcl10 undergoes K63-linked polyubiquitination in response to T cell activation and subsequently binds NEMO, the regulatory subunit of IKK. This interaction requires the ubiquitin-binding activity of NEMO. The sites of Bcl10 ubiquitination were mapped to K31 and K63. Mutation of these residues did not affect TCR signaling-induced CBM complex assembly but prevented Bcl10 ubiquitination, NEMO binding, and NF-kappaB activation. Therefore, the regulated ubiquitination of Bcl10 and its recognition by NEMO are a critical link between the CBM complex, IKK recruitment, and NF-kappaB activation.
Wu
Chuan-Jin
CJ
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Ashwell
Jonathan D
JD
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001665:Binding Sites / Q000235:genetics; D004926:Escherichia coli; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D019169:Jurkat Cells; D008156:Luciferases; D009154:Mutation / Q000235:genetics; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; C491731:IKBKG protein, human; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D011948:Receptors, Antigen, T-Cell; D008156:Luciferases; D051550:I-kappa B Kinase