Journal Article

MALT1 Protease Activity Is Required for Innate and Adaptive Immune Responses

Hughes, Anna C., Beal, Allison M., Finger, Joshua, Rickard, David, Emery, John G., Gough, Peter J., Foley, Kevin P., Ringenberg, Michael A., Berger, Scott B., Bertin, John, Kasparcova, Viera, Hoffman, Sandy, Dykon, Angela, Anderson, Amber D., Yu, Jong W., Ramanjulu, Joshi, Dare, Lauren

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptive immunity / Animals / Antigens / B-Lymphocytes - immunology / Bcl-10 protein / Caspases - genetics / Caspases - metabolism / CD4 antigen / CD8 antigen / Cell proliferation / Defects / Dendritic cells / Dendritic Cells - immunology / Gene Knock-In Techniques / Genes / Homeostasis / Immune response / Immune system / Immunity, Innate / Immunization / Inflammation / Inflammation - genetics / Inflammation - immunology / Interleukin 2 / Kinases / Lymphocyte Activation / Lymphocytes / Lymphocytes B / Lymphocytes T / Lymphoma / Lymphomas / MALT lymphoma / Mice / Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / Mutation / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / NF-κB protein / Organs / Pattern recognition / Peritoneum / Pharmacology / Phosphorylation / Protease / Protease inhibitors / Proteinase inhibitors / Proteins / Receptors / Recruitment / Scaffolding / Signal transduction / Signaling / Signalosomes / Spleen / Spleen - immunology / T cell receptors / T-cell receptor / T-Lymphocytes - immunology / Ubiquitin