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Ubiquitination for Activation: New Directions in the NF-B Roadmap

Department of Micrbiology and Immunology, Queen’s University, Belfast BT9 7BL, Northern Ireland UK

SUMMARY

Signal transduction through the T cell receptor (TCR) and a costimulatory molecule, CD28, results in the stimulation of multiple signaling pathways, leading to the activation of several transcription factors including activator protein–1 (AP-1), nuclear factor of activated T cells (NF-AT), and nuclear factor kappa B (NF-B). The molecular mechanisms by which NF-B is activated by TCR–CD28 have only recently become known. New findings indicate that the adaptor molecules CARMA1 and Bcl10 are essential to the process. Additionally, a critical role for MALT1/paracaspase has been identified. MALT1, CARMA1, and Bcl10 form a tripartite protein complex, in which Bcl10 is thought to facilitate the oligomerization of MALT1 monomers. Overexpression of MALT1, as observed in a subset of lymphoma patients, leads to the potent activation of NF-B, suggesting that MALT1 might stimulate (directly or indirectly) the kinase complex [IKK, inhibitor of NF-B (IB) kinase] responsible for activating cytoplasmic NF-B for translocation into the nucleus. Moreover, the MALT1–CARMA1–Bcl10 complex is responsible for ubiquitination of NEMO, a step that appears to be critical for TCR-induced NF-B activation but not for induction mediated by other stimuli such as TNF or IL-1.

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