Ubiquitination for activation: new directions in the NF-kappaB roadmap.
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-kappaB). The molecular mechanisms by which NF-kappaB 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-kappaB, suggesting that MALT1 might stimulate (directly or indirectly) the kinase complex [IKK, inhibitor of NF-kappaB (IkappaB) kinase] responsible for activating cytoplasmic NF-kappaB 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-kappaB activation but not for induction mediated by other stimuli such as TNF or IL-1.
Lynch
Oonagh T
OT
Department of Micrbiology and Immunology, Queen's University, Belfast BT9 7BL, Northern Ireland, UK.
Gadina
Massimo
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; D018106:CD28 Antigens; C496467:Card11 protein, mouse; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein