Article
- The EMBO Journal (2007) 26, 4634 - 4645
- doi:10.1038/sj.emboj.7601897
Published online: 18 October 2007
Subject Categories:
Malt1 ubiquitination triggers NF-
B signaling upon T-cell activation
Andrea Oeckinghaus1,2,3, Elmar Wegener1, Verena Welteke1, Uta Ferch4, Seda Çöl Arslan2, Jürgen Ruland4, Claus Scheidereit2 and Daniel Krappmann1
- GSF—National Research Center for Environment and Health, Institute of Toxicology, Neuherberg, Germany
- Max-Delbrück—Center for Molecular Medicine, Berlin, Germany
- Faculty of Biology, Chemistry and Pharmacy, Free University Berlin, Germany
- Third Medical Department, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany
Correspondence to:
Daniel Krappmann, GSF—National Research Center for Environment and Health, Institute of Toxicology, Ingolstädter Landstrasse 1, Neuherberg 85764, Germany. Tel.: +49 89 3187 3461; Fax: +49 89 3187 3449; E-mail: Daniel.Krappmann@gsf.de
Received 17 July 2007; Accepted 26 September 2007
Abstract
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 I
B kinase (IKK)/NF-B 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/IKK
. 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-B 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-B pathway.
Keywords:
- Malt1,
- NF-B,
- regulatory ubiquitination,
- T-cell signaling
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