title: MALT1 Protease Activity Is Required for Innate and Adaptive Immune Responses.
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.
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Jong W
authors.initials: JW
authors.lastname: Yu
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Sandy
authors.initials: S
authors.lastname: Hoffman
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Beal
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Dykon
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, King of Prussia, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ringenberg
authors.affiliation: Department of Safety Assessment, GlaxoSmithKline, King of Prussia, United States of America.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Hughes
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Lauren
authors.initials: L
authors.lastname: Dare
authors.affiliation: Quantitative Sciences, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Amber D
authors.initials: AD
authors.lastname: Anderson
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Finger
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Viera
authors.initials: V
authors.lastname: Kasparcova
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Rickard
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Berger
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Joshi
authors.initials: J
authors.lastname: Ramanjulu
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: John G
authors.initials: JG
authors.lastname: Emery
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gough
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Bertin
authors.affiliation: Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, United States of America.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Foley
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D020169:Caspases / Q000235:genetics* / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology; D055879:Gene Knock-In Techniques; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D009363:Neoplasm Proteins; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein