Abstract
The paracaspase MALT1 has a central role in the activation of lymphocytes and other immune cells including myeloid cells, mast cells and NK cells. MALT1 activity is required not only for the immune response, but also for the development of natural Treg cells that keep the immune response in check. Exaggerated MALT1 activity has been associated with the development of lymphoid malignancies, and recently developed MALT1 inhibitors show promising anti-tumor effects in xenograft models of diffuse large B cell lymphoma. In this review, we provide an overview of the present understanding of MALT1’s function, and discuss possibilities for its therapeutic targeting based on recently developed inhibitors and animal models.
Highlights
The paracaspase MALT1 plays an essential role in the activation of immune cells by specific subtypes of immune receptors, which induce a common signaling pathway leading to the activation of the transcription factor NF-jB
MALT1 has an essential role in the immune response and the growth of lymphoma cells with constitutive MALT1 activity
Studies with MALT1-deficient mice and MALT1 inhibitors have suggested that MALT1 could be a rational drug target for immunomodulation and lymphoma treatment
Summary
The paracaspase MALT1 plays an essential role in the activation of immune cells by specific subtypes of immune receptors, which induce a common signaling pathway leading to the activation of the transcription factor NF-jB. A common feature of these patients is combined immunodeficiency, characterized by severe recurrent infections and impaired cellular and humoral immune responses despite normal numbers of circulating B- and T-cells These observations support an essential role for MALT1 in the immune response that is due to its essential signaling function downstream of ITAM-containing immunoreceptors. In non-immune cells, the CARMA1 homologue CARMA3 ( known as CARD10) is thought to play a similar role in promoting BCL10- and MALT1-dependent NF-jB activation downstream of G protein-coupled receptors or the EGFR [24,25,26]. The relevance of MALT1 protease activity for NF-jB activation has been formally demonstrated for receptors depending on CARMA1 or CARD9 [10,11,12,13, 35, 37]; whether it is relevant for CARMA2- and CARMA3dependent NF-jB signals remains uncertain [38]
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