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

作者：Mathijs Baens, Luca Bonsignore, Riet Somers, Charlotte Vanderheydt, S.D. Weeks, Jenny Gunnarsson, Ewa Nilsson, Robert Roth, Margot Thome, Peter Marynen · 发表于：PLoS ONE · 年份：2014 · DOI：10.1371/journal.pone.0103774 · 被引用次数：74 · 研究领域：NF-κB Signaling Pathways、Immune Response and Inflammation、Cytokine Signaling Pathways and Interactions

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.