T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1

Department of Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Zwijnaarde, Ghent, Belgium.
The EMBO Journal (Impact Factor: 10.43). 03/2011; 30(9):1742-52. DOI: 10.1038/emboj.2011.85
Source: PubMed


The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is central to lymphocyte activation and lymphomagenesis. MALT1 mediates antigen receptor signalling to NF-κB by acting as a scaffold protein. Furthermore, MALT1 has proteolytic activity that contributes to optimal NF-κB activation by cleaving the NF-κB inhibitor A20. Whether MALT1 protease activity is involved in other signalling pathways, and the identity of the relevant substrates, is unknown. Here, we show that T-cell receptors (TCR) activation, as well as overexpression of the oncogenic API2-MALT1 fusion protein, results in proteolytic inactivation of CYLD by MALT1, which is specifically required for c-jun N-terminal kinase (JNK) activation and the inducible expression of a subset of genes. These results indicate a novel role for MALT1 proteolytic activity in TCR-induced JNK activation and reveal CYLD cleavage as the underlying mechanism.

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    • "Cleavage of MALT1's binding partner BCL10 does not control NF-κB activity but is thought to affect integrin-mediated T-cell adhesion [31]. Cleavage of CYLD, a de-ubiquitinating enzyme and known negative regulator of NF-κB signaling, was shown to be essential for TCR-induced JNK activation [34]. MCPIP-1 is an RNAse that destabilizes mRNAs of T cell effector genes; its cleavage by MALT1 leads to stabilization of TCR-induced gene transcripts [35]. "
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    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.
    PLoS ONE 08/2014; 9(8):e103774. DOI:10.1371/journal.pone.0103774 · 3.23 Impact Factor
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    • "Next to its scaffold function, MALT1 has recently been shown to also have enzymatic activity [3-7]. In contrast to MALT1’s scaffolding function, its protease activity is not crucial for IKK activation [8], but supports specific TCR-induced gene expression by inactivating negative regulators such as the de-ubiquitinases A20 [3] and CYLD [6], the NF-κB family member RelB [4], and the RNase Regnase-1 [7]. "
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    ABSTRACT: Background The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is crucial for lymphocyte activation through signaling to the transcription factor NF-κB. Besides functioning as a scaffold signaling protein, MALT1 also acts as a cysteine protease that specifically cleaves a number of substrates and contributes to specific T cell receptor-induced gene expression. Recently, small molecule inhibitors of MALT1 proteolytic activity were identified and shown to have promising anticancer properties in subtypes of B cell lymphoma. However, information on the therapeutic potential of small compound inhibitors that target MALT1 protease activity in autoimmunity is still lacking. Methods The present study aimed to elucidate whether MALT1 protease inhibitors are also useful in the treatment of lymphocyte-mediated autoimmune pathologies such as multiple sclerosis (MS). For this, we studied the therapeutic potential of a recently identified inhibitor of MALT1 protease activity, the phenothiazine derivative mepazine, in the context of experimental autoimmune encephalomyelitis (EAE), the main animal model for MS. Results We demonstrate that administration of mepazine prophylactically or after disease onset, can attenuate EAE. Importantly, while complete absence of MALT1 affects the differentiation of regulatory T (Treg) cells in vivo, the MALT1 protease inhibitor mepazine did not affect Treg development. Conclusions Altogether, these data indicate that small molecule inhibitors of MALT1 not only hold great promise for the treatment of B cell lymphomas but also for autoimmune disorders such as MS.
    Journal of Neuroinflammation 07/2014; 11(1):124. DOI:10.1186/1742-2094-11-124 · 5.41 Impact Factor
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    • "The CBM signalosome further recruits signaling components such as TRAF6 for nondegradative polyubiquitination to activate the IkB kinase (IKK), resulting in IkB phosphorylation and degradation, and release of NF-kB proteins for nuclear translocation (Jiang and Lin, 2012). Formation of the CBM signalosome also enables the paracaspase activity of MALT1, which cleaves negative regulators to further enhance NF-kB activity (Coornaert et al., 2008; Hailfinger et al., 2011; Rebeaud et al., 2008; Staal et al., 2011). Nondegradative polyubiquitination that leads to association of Bcl10 with autophagosomes and feedback degradative polyubiquitination of Bcl10 may both result in its gradual degradation and homeostatic control of the pathway (Moreno-García et al., 2013; Paul et al., 2012). "
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    ABSTRACT: The CARMA1/Bcl10/MALT1 (CBM) signalosome mediates antigen receptor-induced NF-κB signaling to regulate multiple lymphocyte functions. While CARMA1 and Bcl10 contain caspase recruitment domains (CARDs), MALT1 is a paracaspase with structural similarity to caspases. Here we show that the reconstituted CBM signalosome is a helical filamentous assembly in which substoichiometric CARMA1 nucleates Bcl10 filaments. Bcl10 filament formation is a highly cooperative process whose threshold is sensitized by oligomerized CARMA1 upon receptor activation. In cells, both cotransfected CARMA1/Bcl10 complex and the endogenous CBM signalosome are filamentous morphologically. Combining crystallography, nuclear magnetic resonance, and electron microscopy, we reveal the structure of the Bcl10 CARD filament and the mode of interaction between CARMA1 and Bcl10. Structure-guided mutagenesis confirmed the observed interfaces in Bcl10 filament assembly and MALT1 activation in vitro and NF-κB activation in cells. These data support a paradigm of nucleation-induced signal transduction with threshold response due to cooperativity and signal amplification by polymerization.
    Molecular cell 09/2013; 51(6):766-79. DOI:10.1016/j.molcel.2013.08.032 · 14.02 Impact Factor
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