The paracaspase MALT1 mediates T cell antigen receptor-induced signaling to the transcription factor NF-kappaB and is indispensable for T cell activation and proliferation. Enhanced expression of MALT1 or aberrant expression of a fusion protein of the apoptosis inhibitor API2 and MALT1 has been linked to mucosa-associated lymphoid tissue lymphoma. Despite the presence of a caspase-like domain, MALT1 proteolytic activity has not yet been demonstrated. Here we show that T cell antigen receptor stimulation induced recruitment of the NF-kappaB inhibitor A20 into a complex of MALT1 and the adaptor protein Bcl-10, leading to MALT1-mediated processing of A20. API2-MALT1 expression likewise resulted in cleavage of A20. MALT1 cleaved human A20 after arginine 439 and impaired its NF-kappaB-inhibitory function. Our studies identify A20 as a substrate of MALT1 and emphasize the importance of MALT1 proteolytic activity in the 'fine tuning' of T cell antigen receptor signaling.

Abstract. Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kB (NF-kB). TLR, IL-1R and TNF-R signaling to NF-kB converge on a common IkB kinase complex that phosphorylates the NF-kB inhibitory protein IkBa. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.Keywords. Toll-like receptor 4, interleukin-1, tumor necrosis factor, NF-kB, signal transduction. NF-kB, does it still need to be introduced?Nuclear factor kB (NF-kB) is the generic name of a family of transcription factors that regulate the expression of a large number of genes involved in immune and inflammatory responses, as well as in cell survival, cell proliferation and cell differentiation. NFkB transcription factors are activated in response to various stimuli, including cytokines, infectious agents, injury and other stressful conditions requiring rapid reprogramming of gene expression. Inappropriate activation of the NF-kB signaling pathway is implicated in the pathogenesis of chronic inflammation and autoimmunity, certain hereditary disorders and various cancers. In mammals, the NF-kB family consists of five proteins sharing a highly conserved Rel homology domain: c-Rel, RelB, p65 (= RelA), p105 (= NF-kB1) and p100 (=NF-kB2). The first three contain Cterminal transactivation domains, while the others share a long C-terminal domain with multiple copies of ankyrin repeats, which inhibit their activation.

The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is central to lymphocyte activation and lymphomagenesis. MALT1 mediates antigen receptor signalling to NF-jB by acting as a scaffold protein. Furthermore, MALT1 has proteolytic activity that contributes to optimal NF-jB activation by cleaving the NF-jB inhibitor A20. Whether MALT1 protease activity is involved in other signalling pathways, and the identity of the relevant substrates, is unknown. Here, we show that T-cell receptors (TCR) activation, as well as overexpression of the oncogenic API2-MALT1 fusion protein, results in proteolytic inactivation of CYLD by MALT1, which is specifically required for c-jun N-terminal kinase (JNK) activation and the inducible expression of a subset of genes. These results indicate a novel role for MALT1 proteolytic activity in TCRinduced JNK activation and reveal CYLD cleavage as the underlying mechanism.