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

ABSTRACT: Mucosa-associated lymphoid tissue 1 (MALT1) controls antigen receptor-mediated signalling to nuclear factor ?B (NF-?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?B? phosphorylation and NF-?B nuclear translocation. Parallel induction of MALT1 protease activity serves to inactivate negative regulators of NF-?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?B? phosphorylation and normal nuclear accumulation of NF-?B subunits. Nevertheless, MALT1 cleavage was required for optimal activation of NF-?B reporter genes and expression of the NF-?B targets IL-2 and CSF2. Transcriptome analysis confirmed that MALT1 cleavage after R149 was required to induce NF-?B transcriptional activity in Jurkat T cells. Collectively, these data demonstrate that auto-proteolytic MALT1 cleavage controls antigen receptor-induced expression of NF-?B target genes downstream of nuclear NF-?B accumulation.

SUBMITTER: Baens M 

PROVIDER: S-EPMC4126661 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature