Lymphocyte signaling and activation by the CARMA1-BCL10-MALT1 signalosome

Abstract

Abstract:The CARMA1-BCL10-MALT1 (CBM) signalosome triggers canonical NF-κB signaling and lymphocyte activation upon antigen-receptor stimulation. Genetic studies in mice and the analysis of human immune pathologies unveiled a critical role of the CBM complex in adaptive immune responses. Great progress has been made in elucidating the fundamental mechanisms that dictate CBM assembly and disassembly. By bridging proximal antigenreceptor signaling to downstream signaling pathways, the CBM complex exerts a crucial scaffolding function. Moreover, the MALT1 subunit confers a unique proteolytic activity that is key for lymphocyte activation. Deregulated 'chronic' CBM signaling drives constitutive NF-κB signaling and MALT1 activation, which contribute to the development of autoimmune and inflammatory diseases as well as lymphomagenesis. Thus, the processes that govern CBM activation and function are promising targets for the treatment of immune disorders. Here, we summarize the current knowledge on the functions and mechanisms of CBM signaling in lymphocytes and how CBM deregulations contribute to aberrant signaling in malignant lymphomas.

A CARD10-Dependent Tonic Signalosome Activates MALT1 Paracaspase and Regulates IL-17/TNF-α–Driven Keratinocyte Inflammation

“…The paracaspase MALT1 controls signaling downstream of several cell surface receptors, such as C-type lectin receptors on myeloid cells and antigen receptors on lymphocytes. Upon receptor engagement, MALT1, BCL10, and a CARD family member assemble into a "CBM complex," which is required to trigger MALT1 paracaspase activity and downstream transcriptional activation mechanisms (Meininger and Krappmann, 2016;Rosebeck et al, 2011). Here, we found that CARD10 is highly expressed in proliferating keratinocytes and is responsible for a tonic level of paracaspase activity, driven by MALT1 isoform A.…”

Holding All the CARDs: How MALT1 Controls CARMA/CARD-Dependent Signaling

“…Once assembled, the CBM complex acts as a signaling platform for the recruitment of multiple signaling complexes, including TRAF6, the TAB1/2-TAK1 complex, the IKK complex, and the linear ubiquitin chain assembly complex (LUBAC) (51). These control various aspects of signal transmission that are essential for NF-κB and AP-1 activation.…”

Inhibition of MALT1 paracaspase activity improves lesion recovery following spinal cord injury

“…Our C472G mice (number based on MALT1 isoform B) are, in fact, equivalent to the previously described C472A KI mice (number based on MALT1 isoform A) [38], except for replacing the cysteine by a glycine, rather than by an alanine. Both isoforms exist and are differentially regulated [39]. The C472G KI mice were back crossed with C57BL/6J for at least 5 generations.…”