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The activation and proliferation of lymphocytes requires the antigen receptor-mediated activation of a transcription factor, NF-kB, which controls the expression of proliferation- and survival-promoting genes. CARMA1, BCL10 and MALT1 form a complex of signaling proteins (also called the CBM complex) that plays an essential role in the activation of the NF-kB pathway in antigen-stimulated lymphocytes (Rosebeck et al., 2011b; Thome et al., 2010). Genetic evidence from knock-out mice supports the idea that each of the three CBM proteins is required for the efficient generation of the adaptive immune response. There is also good evidence for an oncogenic role of the CBM proteins in the formation of human B-cell lymphomas of the mucosa-associated lymphoid tissue (so-called MALT lymphomas) and diffuse large B-cell lymphomas (DLBCL) (Rosebeck et al., 2011b). We have recently shown that MALT1 has protease activity that is transiently induced in activated lymphocytes in a CARMA1- and BCL10- dependent manner, and we have identified BCL10 and RelB as MALT1 substrates that control different aspects of lymphocyte activation (Hailfinger et al., 2011; Rebeaud et al., 2008). Moreover, we could show that the viability and proliferation of B-cell lines derived from ABC-DLBCL critically depends on constitutive oncogenic MALT1 activity and the cleavage of RelB (Hailfinger et al., 2009; Hailfinger et al., 2011). Collectively, these findings have identified the protease activity of MALT1 as a candidate drug target for immunomodulation and for the treatment of particular subtypes of human lymphomas characterized by constitutive MALT1 activity. However, the exact mechanism by which MALT1 promotes lymphocyte proliferation, and the full elucidation of its relevant substrates remain challenging tasks. Here we propose to address these issues by (1) the identification and characterization of new MALT1 substrates, (2) the identification of MALT1 regulators and (3) the characterization of the immune phenotype of mice expressing a catalytically inactive version of MALT1.By the elucidation of the molecular and physiological role of MALT1, we expect to significantly contribute to the understanding of the mechanisms that control normal lymphocyte activation and its deregulation in autoimmune diseases or lymphomas. Moreover, a better comprehension of these mechanisms could potentially allow the rational design of MALT1-inhibiting drugs with immunosuppressive or anti-lymphoma activity.