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: 31.48). 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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    • "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.
    PLoS ONE 08/2014; 9(8):e103774. DOI:10.1371/journal.pone.0103774 · 3.23 Impact Factor
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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.
    Journal of Neuroinflammation 07/2014; 11(1):124. DOI:10.1186/1742-2094-11-124 · 4.90 Impact Factor
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    • "Several studies showed that loss-of-function mutations of TRAF2, TRAF3 or cIAP1/2 protects NIK from proteasomal degradation leading to accumulation of NIK and subsequent constitutive noncanonical NF-κB activation in multiple myeloma cells [5], [6]. A recent report also demonstrated a mechanism of deregulated NIK activity showing that a fusion oncoprotein of apoptosis inhibitor 2 and mucosa associated lymphoid tissue lymphoma translocation gene 1 cleaves NIK at R325 resulting in production of NIK lacking the TRAF3-binding site, which enables constitutive noncanonical NF-κB signaling in MALT lymphoma [34]. In our present study, the NIK protein was barely detectable without treatment of ovarian cancer cells with the proteasome inhibitor MG132, indicating a rapid turnover of the NIK protein in those cells. "
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    ABSTRACT: Ovarian cancer is one of the leading causes of female death and the development of novel therapeutic approaches is urgently required. Nuclear factor-κB (NF-κB) is constitutively activated in several types of cancer including ovarian cancer and is known to support the survival of cancer cells. However, molecular mechanisms of persistent activation of NF-κB in ovarian cancer remain largely unknown. We report here that, in addition to the previously reported canonical activation, NF-κB is activated through the noncanonical pathway in ovarian cancer cells. RNA interference-mediated silencing of NF-κB inducing kinase (NIK), a central regulator of the noncanonical pathway, reduced the NF-κB2/p52 DNA binding activity and NF-κB-dependent reporter gene expression as well as NF-κB target gene expression. Notably, anchorage-dependent and -independent cell growth was impaired in NIK-depleted cells. Depletion of NIK also suppressed tumor formation in the nude mouse xenograft assay. These results indicate that NIK plays a key role in constitutive NF-κB activation and the progression of ovarian cancer cells and suggest that NIK represents an attractive therapeutic target for ovarian cancer.
    PLoS ONE 02/2014; 9(2):e88347. DOI:10.1371/journal.pone.0088347 · 3.23 Impact Factor
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