MALT1 Auto-Proteolysis Is Essential for NF-κB-Dependent Gene Transcription in Activated Lymphocytes

Mucosa-associated lymphoid tissue 1 (MALT1) controls antigen receptor-mediated signalling to nuclear factor kappa B (NF-kappa B) through both its adaptor and protease function. Upon antigen stimulation, MALT1 forms a complex with BCL10 and CARMA1, which is essential for initial I kappa B alpha phosphorylation and NF-kappa B nuclear translocation. Parallel induction of MALT1 protease activity serves to inactivate negative regulators of NF-kappa B 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 I kappa B alpha phosphorylation and normal nuclear accumulation of NF-kappa B subunits. Nevertheless, MALT1 cleavage was required for optimal activation of NF-kappa B reporter genes and expression of the NF-kappa B targets IL-2 and CSF2. Transcriptome analysis confirmed that MALT1 cleavage after R14(was required to induce NF-kappa B transcriptional activity in Jurkat T cells. Collectively, these data demonstrate that auto-proteolytic MALT1 cleavage controls antigen receptor-induced expression of NF-kappa B target genes downstream of nuclear NF-kappa B accumulation.