Article

Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation

Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI 48109, USA.
Science (Impact Factor: 33.61). 01/2011; 331(6016):468-72. DOI: 10.1126/science.1198946
Source: PubMed

ABSTRACT

Proper regulation of nuclear factor κB (NF-κB) transcriptional activity is required for normal lymphocyte function, and deregulated
NF-κB signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent
t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-κB–inducing kinase
(NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK
fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity
is associated with constitutive noncanonical NF-κB signaling, enhanced B cell adhesion, and apoptosis resistance. Our study
reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical
NF-κB pathway in B lymphoproliferative disease.

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    • "Future studies will need to determine in how far detection of MALT1 activity can facilitate diagnosis and therapeutic decisions in other lymphoid malignancies. Besides DLBCL, chromosomal MALT1 translocations and MALT1 activity contribute to MALT lymphoma (Rosebeck et al., 2011), and MALT1 activity may be potentially enhanced in mantle cell lymphoma that are sensitive to the BTK inhibitor ibrutinib (Rahal et al., 2014). Thus, MALT1 activity could serve as an additional biomarker for different lymphoma entities or to monitor patient responses to pharmacological inhibitors targeting directly MALT1 or upstream regulators. "
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    ABSTRACT: MALT1 paracaspase is activated upon antigen receptor stimulation to promote lymphocyte activation. In addition, deregulated MALT1 protease activity drives survival of distinct lymphomas such as the activated B cell type of diffuse large B cell lymphoma (ABC-DLBCL). Here, we designed fluorophore or biotin-coupled activity based-probes (ABP) that covalently modify the active center of MALT1. MALT1-ABPs are exclusively labeling an active modified full length form of MALT1 upon T cell stimulation. Further, despite the CARMA1 requirement for initial MALT1 activation, the MALT1-ABPs show that protease activity is not confined to the high-molecular CARMA1-BCL10-MALT1 (CBM) complex. Using biotin-coupled ABPs, we developed a robust assay for sensitive and selective detection of active MALT1 in cell lines, primary lymphocytes, and DLBCL tumor biopsies. Taken together, MALT1-ABPs represent powerful chemical tools to measure cellular MALT1 activation, determine efficacy of small molecule inhibitors, and classify lymphomas based on MALT1 activity status.
    No preview · Article · Dec 2014 · Chemistry & Biology
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    • "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]. Finally, cleavage of NIK by the API2-MALT1 fusion protein activates non-canonical NF-κB signaling, which contributes together with canonical NF-κB activation to MALT lymphomagenesis [36]. MALT1 protease activity is also essential for the survival of cells derived from the activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL) [37], [38], which are addicted to constant MALT1-driven NF-κB signaling [39]. "
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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.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "At the cellular level, MALT1 proteolytic activity has been implicated in MALT lymphoma and activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL) [3,9-11]. In this context, treatment of ABC-DLBCL cells with the MALT1 protease peptide inhibitor z-VRPR-fmk reduces constitutive NF-κB activity and cell proliferation [12,13]. "
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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.
    Full-text · Article · Jul 2014 · Journal of Neuroinflammation
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