The paracaspase MALT1 is pivotal in antigen receptor-mediated lymphocyte activation and lymphomagenesis. MALT1 contains a caspase-like domain, but it is unknown whether this domain is proteolytically active. Here we report that MALT1 had arginine-directed proteolytic activity that was activated after T cell stimulation, and we identify the signaling protein Bcl-10 as a MALT1 substrate. Processing of Bcl-10 after Arg228 was required for T cell receptor-induced cell adhesion to fibronectin. In contrast, MALT1 activity but not Bcl-10 cleavage was essential for optimal activation of transcription factor NF-kappaB and production of interleukin 2. Thus, the proteolytic activity of MALT1 is central to T cell activation, which suggests a possible target for the development of immunomodulatory or anticancer drugs.

The signaling pathway controlling antigen receptor-induced regulation of the transcription factor NF-kB plays a key role in lymphocyte activation and development and the generation of lymphomas. Work of the past decade has led to dramatic progress in the identification and characterization of new players in the pathway. Moreover, novel enzymatic activities relevant for this pathway have been discovered, which represent interesting drug targets for immuno-suppression or lymphoma treatment. Here, we summarize these findings and give an outlook on interesting open issues that need to be addressed in the future.

Hepatocytes play a pivotal role in both the synthesis and degradation of numerous endogenous biomolecules, thus maintaining metabolic homeostasis, as well as in the conversion and detoxification of xenobiotic compounds. Based on the location of the blood vessels, the terminal branches of the portal and the hepatic (central) veins and on the direction of the blood flow, hepatocytes of each liver lobule can be divided into two subpopulations, an upstream 'periportal' and a downstream 'perivenous' (pericentral) population. Zonal-specific differences in the metabolic capacities of many enzymes or other proteins, and -to a lesser extent ) of their corresponding messenger RNAs, have been subject to extensive studies throughout the last decades.Many enzymes of intermediary metabolism are not distributed uniformly throughout the liver, but are preferentially expressed in either the periportal or the perivenous hepatocyte subpopulation [1][2][3]. Hence, hepatocytes located in either of the two regions have different, often complementary, functions. Whereas, for example, glycolysis is exclusively active in perivenous hepatocytes, key enzymes of gluconeogenesis, the antagonist pathway, are preferentially expressed in periportal hepatocytes [1]. Zonal-specific expression has also been established for enzymes of amino acid and ammonia metabolism, showing, for example, a higher activity of the urea cycle in periportal cells compared to perivenous hepatocytes [3], whereas glutamine synthesis is exclusively active in the perivenous Hepatocytes located in the periportal and perivenous zones of the liver lobule show remarkable differences in the levels and activities of various enzymes and other proteins. To analyze global gene expression patterns of periportal and perivenous hepatocytes, enriched populations of the two cell types were isolated by combined collagenase ⁄ digitonin perfusion from mouse liver and used for microarray analysis. In total, 198 genes and expressed sequences were identified that demonstrated a ‡ 2-fold difference in expression between hepatocytes from the two different zones of the liver. A subset of 20 genes was additionally analyzed by real-time RT-PCR, validating the results obtained by the microarray analysis. Several of the differentially expressed genes encoded key enzymes of intermediary metabolism, including those involved in glycolysis and gluconeogenesis, fatty acid degradation, cholesterol and bile acid metabolism, amino acid degradation and ammonia utilization. In addition, several enzymes of phase I and phase II of xenobiotic metabolism were differentially expressed in periportal and perivenous hepatocytes. Our results confirm previous findings on metabolic zonation in liver, and extend our knowledge of the regulatory mechanisms at the transcriptional level.Abbreviations GS, glutamine synthetase.

The protease activity of the paracaspase Malt1 contributes to antigen receptor-mediated lymphocyte activation and lymphomagenesis. Malt1 activity is required for optimal NF-κB activation, but little is known about the responsible substrate(s). Here we report that Malt1 cleaved the NF-κB family member RelB after Arg-85. RelB cleavage induced its proteasomal degradation and specifically controlled DNA binding of RelA-or c-Rel-containing NF-κB complexes. Overexpression of RelB inhibited expression of canonical NF-κB target genes and led to impaired survival of diffuse large B-cell lymphoma cell lines characterized by constitutive Malt1 activity. These findings identify a central role for Malt1-dependent RelB cleavage in canonical NF-κB activation and thereby provide a rationale for the targeting of Malt1 in immunomodulation and cancer treatment.signal transduction | T-cell receptor T he antigen receptor-driven activation of the nuclear factorkappa B (NF-κB) signaling pathway has recently gained considerable interest because genetic deficiencies in this pathway are linked to immune deficiencies, whereas aberrant constitutive NF-κB activation is associated with the development of autoimmune disease and neoplastic disorders (1-4).The NF-κB family of transcription factors comprises five transcription factors that share a Rel homology domain (RHD) required for DNA binding and homo-or heterodimerization (1, 5). The transcriptionally active form of NF-κB is a heterodimer containing a member with an RHD (p50 or p52) and one with an RHD and an additional transcription activation domain (RelA, RelB, or c-Rel). NF-κB family members are present in the cytoplasm in an inactive form that can be mobilized by either the classical (canonical) or alternative (noncanonical) pathway. The classical pathway is thought to control the activation of p50-RelA and p50-c-Rel complexes by stimulus-dependent degradation of inhibitor of κB (IκB) proteins that bind these complexes and prevent their nuclear translocation. The alternative pathway, on the other hand, controls the generation of transcriptionally active p52-RelB complexes through stimulationinduced processing of the p52 precursor p100 (5).T-cell receptor (TCR)-induced NF-κB activation has been shown to rely on the activation of both RelA-and c-Rel-containing NF-κB complexes that occur in a timely staggered manner (6). However, the exact mechanism controlling persistent RelA-p50 and c-Rel-p50 activation in T cells remains not well characterized.Biochemical and genetic studies have identified an essential role for proteins of the Carma1/Bcl-10/Malt1 (CBM) signaling module in TCR-induced NF-κB activation (2, 7-9). The current model of CBM-dependent NF-κB activation suggests that antigen triggering leads to the phosphorylation of Carma1 by PKC family and probably additional kinases, inducing a conformational change in Carma1 that allows it to recruit preformed Bcl-10/Malt1 complexes (7, 10). Malt1 is thought to control the activation of the IKK complex by binding to the ubiquitin ligase T...

A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy.