Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation.

Triggering of antigen receptors on lymphocytes is critical for initiating adaptive immune response against pathogens. T-cell receptor (TCR) engagement induces the formation of the Carma1-Bcl10-Malt1 (CBM) complex that is essential for activation of the IkappaB kinase (IKK)/NF-kappaB pathway. However, the molecular mechanisms that link CBM complex formation to IKK activation ...
remain unclear. Here we report that Malt1 is polyubiquitinated upon T-cell activation. Ubiquitin chains on Malt1 provide a docking surface for the recruitment of the IKK regulatory subunit NEMO/IKKgamma. TRAF6 associates with Malt1 in response to T-cell activation and can function as an E3 ligase for Malt1 in vitro and in vivo, mediating lysine 63-linked ubiquitination of Malt1. Multiple lysine residues in the C-terminus of Malt1 serve as acceptor sites for the assembly of polyubiquitin chains. Malt1 mutants that lack C-terminal ubiquitin acceptor lysines are impaired in rescuing NF-kappaB signaling and IL-2 production in Malt1-/- T cells. Thus, our data demonstrate that induced Malt1 ubiquitination is critical for the engagement of CBM and IKK complexes, thereby directing TCR signals to the canonical NF-kappaB pathway.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Apoptosis Regulatory Proteins, CARD Signaling Adaptor Proteins, Caspases, Cell Line, Guanylate Cyclase, Humans, I-kappa B Kinase, Interleukin-2, Jurkat Cells, NF-kappa B, Neoplasm Proteins, T-Lymphocytes, TNF Receptor-Associated Factor 6, Ubiquitination
EMBO J.
Date: Nov. 14, 2007
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