MALT1 Is an Essential Regulator of Antigen Receptor Mediated NF-kappaB Activation.

The translocation t(11;18)(q21;q21) is the most common chromosomal abnormality in lymphomas of mucosa associated lymphoid tissue (MALT lymphoma). Molecular cloning of the breakpoint demonstrated that t(11;18) leads to the fusion of the IAP2 gene to the novel gene MALT1. MALT1 encodes a paracaspase that can bind to BCL10 but its cellular function was unknown. We have previously demonstrated that BCL10, which is involved in independent MALT lymphoma translocations, functions as a positive regulator of lymphocyte proliferation. BCL10 connects antigen receptor signaling in B and T cells to NF-kappa B activation. To identify the physiological role of MALT1 we have now disrupted the MALT1 gene in mice. Here we are using both MALT1 and BCL10 deficient animals and show that MALT1 is essential for functional T cell activation, proliferation and cytokine production in response to T cell receptor (TCR) ligation. Similar to BCL10 we found MALT1 to be strictly required for signal-specific NF-kappaB activation in response to TCR ligation but not for TNF-alpha or IL-1 signaling. MALT1 operates downstream of BCL10, controls the catalytic activity of IKK and additionally regulates signaling of p38 and JNK MAP kinases. Moreover we found MALT1 to be critical for B1 and marginal zone (MZ) B cell development. In contrast to BCL10 disruption however, inactivation of MALT1 has only mild effects on conventional B2 B cell activation, BCR induced NF-kappaB signaling in splenic B lymphocytes and does not cause defects during embryonic development. Thus, MALT1 is an essential regulator of BCL10 mediated NF-kB induction that is differentially required depending on the cellular context. Together these data support the view that normal expression of BCL10 and MALT1 are necessary for controlled NF-kB signaling in lymphocytes whereas deregulation of either BCL10 or MALT1 through chromosomal translocation results in increased lymphocyte growth and survival