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...

Inflammation is a protective attempt by the host to remove injurious stimuli and initiate the tissue healing process. The inflammatory response must be actively terminated, however, because failure to do so can result in 'bystander' damage to tissues and diseases such as arthritis or type-2 diabetes. Yet the mechanisms controlling excessive inflammatory responses are still poorly understood. Here we show that mouse effector and memory CD4(+) T cells abolish macrophage inflammasome-mediated caspase-1 activation and subsequent interleukin 1beta release in a cognate manner. Inflammasome inhibition is observed for all tested NLRP1 (commonly called NALP1) and NLRP3 (NALP3 or cryopyrin) activators, whereas NLRC4 (IPAF) inflammasome function and release of other inflammatory mediators such as CXCL2, interleukin 6 and tumour necrosis factor are not affected. Suppression of the NLRP3 inflammasome requires cell-to-cell contact and can be mimicked by macrophage stimulation with selected ligands of the tumour necrosis factor family, such as CD40L (also known as CD40LG). In a NLRP3-dependent peritonitis model, effector CD4(+) T cells are responsible for decreasing neutrophil recruitment in an antigen-dependent manner. Our findings reveal an unexpected mechanism of inflammasome inhibition, whereby effector and memory T cells suppress potentially damaging inflammation, yet leave the primary inflammatory response, crucial for the onset of immunity, intact.

No abstract

The mucosa-associated lymphoid tissue protein-1 (MALT1, also known as paracaspase) is a protease whose activity is essential for the activation of lymphocytes and the growth of cells derived from human diffuse large B-cell lymphomas of the activated B-cell subtype (ABC DLBCL). Crystallographic approaches have shown that MALT1 can form dimers via its protease domain, but why dimerization is relevant for the biological activity of MALT1 remains largely unknown. Using a molecular modeling approach, we predicted Glu 549 (E549) to be localized within the MALT1 dimer interface and thus potentially relevant. Experimental mutation of this residue into alanine (E549A) led to a complete impairment of MALT1 proteolytic activity. This correlated with an impaired capacity of the mutant to form dimers of the protease domain in vitro, and a reduced capacity to promote NF-κB activation and transcription of the growth-promoting cytokine interleukin-2 in antigen receptor-stimulated lymphocytes. Moreover, this mutant could not rescue the growth of ABC DLBCL cell lines upon MALT1 silencing. Interestingly, the MALT1 mutant E549A was unable to undergo monoubiquitination, which we identified previously as a critical step in MALT1 activation. Collectively, these findings suggest a model in which E549 at the dimerization interface is required for the formation of the enzymatically active, monoubiquitinated form of MALT1.