title: MALT1 auto-proteolysis is essential for NF-κB-dependent gene transcription in activated lymphocytes.
abstract: Mucosa-associated lymphoid tissue 1 (MALT1) controls antigen receptor-mediated signalling to nuclear factor κB (NF-κB) through both its adaptor and protease function. Upon antigen stimulation, MALT1 forms a complex with BCL10 and CARMA1, which is essential for initial IκBα phosphorylation and NF-κB nuclear translocation. Parallel induction of MALT1 protease activity serves to inactivate negative regulators of NF-κB signalling, such as A20 and RELB. Here we demonstrate a key role for auto-proteolytic MALT1 cleavage in B- and T-cell receptor signalling. MALT1 cleavage occurred after Arginine 149, between the N-terminal death domain and the first immunoglobulin-like region, and did not affect its proteolytic activity. Jurkat T cells expressing an un-cleavable MALT1-R149A mutant showed unaltered initial IκBα phosphorylation and normal nuclear accumulation of NF-κB subunits. Nevertheless, MALT1 cleavage was required for optimal activation of NF-κB reporter genes and expression of the NF-κB targets IL-2 and CSF2. Transcriptome analysis confirmed that MALT1 cleavage after R149 was required to induce NF-κB transcriptional activity in Jurkat T cells. Collectively, these data demonstrate that auto-proteolytic MALT1 cleavage controls antigen receptor-induced expression of NF-κB target genes downstream of nuclear NF-κB accumulation.
authors.affiliation: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Mathijs
authors.initials: M
authors.lastname: Baens
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Bonsignore
authors.affiliation: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Riet
authors.initials: R
authors.lastname: Somers
authors.affiliation: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Vanderheydt
authors.affiliation: Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weeks
authors.affiliation: Reagent and Assay Development, Discovery Sciences, Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Gunnarsson
authors.affiliation: Reagent and Assay Development, Discovery Sciences, Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Ewa
authors.initials: E
authors.lastname: Nilsson
authors.affiliation: Reagent and Assay Development, Discovery Sciences, Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roth
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Margot
authors.initials: M
authors.lastname: Thome
authors.affiliation: Human Genome Laboratory, Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001483:Base Sequence; D015153:Blotting, Western; D020169:Caspases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008214:Lymphocytes / Q000378:metabolism*; D008969:Molecular Sequence Data; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D020125:Mutation, Missense / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059748:Proteolysis; D060888:Real-Time Polymerase Chain Reaction; D011946:Receptors, Antigen / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics* / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011946:Receptors, Antigen; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
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