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PLoS One. 2014 Aug 8;9(8):e103774. doi: 10.1371/journal.pone.0103774. eCollection 2014.

MALT1 auto-proteolysis is essential for NF-κB-dependent gene transcription in activated lymphocytes.

Author information

1
Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Center for Human Genetics, KU Leuven, Leuven, Belgium.
2
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
3
Laboratory for Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
4
Reagent and Assay Development, Discovery Sciences, Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
5
Human Genome Laboratory, Center for Human Genetics, KU Leuven, Leuven, Belgium.

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.

PMID:
25105596
PMCID:
PMC4126661
DOI:
10.1371/journal.pone.0103774
[Indexed for MEDLINE]
Free PMC Article

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