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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • B-Cell CLL-Lymphoma 10 Protein
  • Base Sequence
  • Blotting, Western
  • Caspases / genetics
  • Caspases / metabolism
  • Caspases / physiology*
  • Cell Membrane / metabolism
  • Fluorescence Resonance Energy Transfer
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Jurkat Cells
  • Lymphocytes / metabolism*
  • Molecular Sequence Data
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • Mutation, Missense / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology*
  • Proteolysis
  • Real-Time Polymerase Chain Reaction
  • Receptors, Antigen / metabolism
  • Sequence Analysis, RNA
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Transcription, Genetic / genetics*
  • Transcription, Genetic / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • B-Cell CLL-Lymphoma 10 Protein
  • BCL10 protein, human
  • NF-kappa B
  • Neoplasm Proteins
  • Receptors, Antigen
  • Caspases
  • MALT1 protein, human
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein

Associated data

  • GEO/GSE52934

Grants and funding

Work in Mathijs Baens'/Peter Marynen's laboratory is supported by research grants from the FWO (G.0534.12), the ‘Belgian Foundation against Cancer' (190-2008) and the ‘Concerted Research Actions' (GOA grant GOA/11/010). The Thome laboratory is supported by grants from the Swiss National Science Foundation and Oncosuisse. The Helmut Horten Foundation supports Luca Bonsignore and Margot Thome. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.