Nuclear factor-kB (NF-kB) consists of a family of transcription factors that play critical roles in inflammation, immunity, cell proliferation, differentiation, and survival. Inducible NF-kB activation depends on phosphorylation-induced proteosomal degradation of the inhibitor of NF-kB proteins (IkBs), which retain inactive NF-kB dimers in the cytosol in unstimulated cells. The majority of the diverse signaling pathways that lead to NF-kB activation converge on the IkB kinase (IKK) complex, which is responsible for IkB phosphorylation and is essential for signal transduction to NF-kB. Additional regulation of NF-kB activity is achieved through various post-translational modifications of the core components of the NF-kB signaling pathways. In addition to cytosolic modifications of IKK and IkB proteins, as well as other pathway-specific mediators, the transcription factors are themselves extensively modified. Tremendous progress has been made over the last two decades in unraveling the elaborate regulatory networks that control the NF-kB response. This has made the NF-kB pathway a paradigm for understanding general principles of signal transduction and gene regulation.

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The Carma1-Bcl10-Malt1 signaling module bridges TCR signaling to the canonical IκB kinase (IKK)/NF-κB pathway. Covalent attachment of regulatory ubiquitin chains to Malt1 paracaspase directs TCR signaling to IKK activation. Further, the ubiquitin-editing enzyme A20 was recently suggested to suppress T cell activation, but molecular targets for A20 remain elusive. In this paper, we show that A20 regulates the strength and duration of the IKK/NF-κB response upon TCR/CD28 costimulation. By catalyzing the removal of K63-linked ubiquitin chains from Malt1, A20 prevents sustained interaction between ubiquitinated Malt1 and the IKK complex and thus serves as a negative regulator of inducible IKK activity. Upon T cell stimulation, A20 is rapidly removed and paracaspase activity of Malt1 has been suggested to cleave A20. Using antagonistic peptides or reconstitution of Malt1−/− T cells, we show that Malt1 paracaspase activity is required for A20 cleavage and optimal IL-2 production, but dispensable for initial IKK/NF-κB signaling in CD4+ T cells. However, proteasomal inhibition impairs A20 degradation and impedes TCR/CD28-induced IKK activation. Taken together, A20 functions as a Malt1 deubiquitinating enzyme and proteasomal degradation and de novo synthesis of A20 contributes to balance TCR/CD28-induced IKK/NF-κB signaling.

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 IκB kinase (IKK)/NF‐κB 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/IKKγ. 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‐κB 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‐κB pathway.