Abstract
CARMA-BCL10-MALT1 signalosomes play important roles in antigen receptor signaling and other pathways. Previous studies have suggested that as part of this complex, MALT1 functions as both a scaffolding protein to activate NF-κB through recruitment of ubiquitin ligases, and as a protease to cleave and inactivate downstream inhibitory signaling proteins. However, our understanding of the relative importance of these two distinct MALT1 activities has been hampered by a lack of selective MALT1 protease inhibitors with suitable pharmacologic properties. To fully investigate the role of MALT1 protease activity, we generated mice homozygous for a protease-dead mutation in MALT1. We found that some, but not all, MALT1 functions in immune cells were dependent upon its protease activity. Protease-dead mice had defects in the generation of splenic marginal zone and peritoneal B1 B cells. CD4+ and CD8+ T cells displayed decreased T cell receptor-stimulated proliferation and IL-2 production while B cell receptor-stimulated proliferation was partially dependent on protease activity. In dendritic cells, stimulation of cytokine production through the Dectin-1, Dectin-2, and Mincle C-type lectin receptors was also found to be partially dependent upon protease activity. In vivo, protease-dead mice had reduced basal immunoglobulin levels, and showed defective responses to immunization with T-dependent and T-independent antigens. Surprisingly, despite these decreased responses, MALT1 protease-dead mice, but not MALT1 null mice, developed mixed inflammatory cell infiltrates in multiple organs, suggesting MALT1 protease activity plays a role in immune homeostasis. These findings highlight the importance of MALT1 protease activity in multiple immune cell types, and in integrating immune responses in vivo.
Highlights
The discovery that the MALT1 (Entrez Gene ID 10892) and BCL10 genes are involved in translocations commonly found in B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) in turn led to the identification of the so-called ‘CBM signalosome’, which is a heterotrimeric complex between any one of several different members of the CARMA protein family, with BCL10 and MALT1 [1]
To determine if lymphocyte development is dependent upon MALT1 protease function, we examined the abundance of the major T and B cell populations by flow cytometry
The B1 B cell (IgMhiCD5lo) population was almost completely absent in peritoneal fluid of Malt1-/- and Malt1PD/PD mice (Fig 2E and 2G). These results are consistent with those previously reported for Malt1-/- mice [14,15], and indicate that MALT1 is not required for T cell and follicular B cell maturation in the spleen
Summary
The discovery that the MALT1 (Entrez Gene ID 10892) and BCL10 genes are involved in translocations commonly found in B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) in turn led to the identification of the so-called ‘CBM signalosome’, which is a heterotrimeric complex between any one of several different members of the CARMA protein family, with BCL10 and MALT1 [1]. In T and B lymphocytes, antigen receptor engagement results in stimulation of the canonical NF-κB signaling pathway. This is due in part to Protein Kinase C-mediated phosphorylation of CARMA1 and its assembly into a CBM signalosome [1,8,9]. As part of the CBM complex, oligomerized MALT1 acts as a scaffold to recruit critical downstream signaling proteins, such as the ubiquitin ligase TRAF6 which enables K63-polyubiquitination of the regulatory subunit of IKK, NEMO, leading to phosphorylation of IκB [10,11,12,13]. The ensuing proteosomal degradation of IκB permits NF-κB nuclear translocation and transcription of genes involved in lymphocyte proliferation, differentiation, and effector functions
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