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

EMBO J. 2007 Nov 14;26(22):4634-45. doi: 10.1038/sj.emboj.7601897. Epub 2007 Oct 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis Regulatory Proteins / metabolism
  • B-Cell CLL-Lymphoma 10 Protein
  • CARD Signaling Adaptor Proteins / metabolism
  • Caspases / metabolism*
  • Cell Line
  • Guanylate Cyclase / metabolism
  • Humans
  • I-kappa B Kinase / metabolism
  • Interleukin-2 / metabolism
  • Jurkat Cells
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / metabolism*
  • T-Lymphocytes / metabolism
  • TNF Receptor-Associated Factor 6 / metabolism
  • Ubiquitination


  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • B-Cell CLL-Lymphoma 10 Protein
  • BCL10 protein, human
  • CARD Signaling Adaptor Proteins
  • Interleukin-2
  • NF-kappa B
  • Neoplasm Proteins
  • TNF Receptor-Associated Factor 6
  • I-kappa B Kinase
  • Caspases
  • MALT1 protein, human
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • CARD11 protein, human
  • Guanylate Cyclase