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MALT1/Paracaspase is a signaling component downstream of CARMA1 and mediates T cell receptor-induced NF-kappa B activation

Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2004; 279(16):15870-6. DOI: 10.1074/jbc.M310599200
Source: PubMed

ABSTRACT T cell receptor (TCR) induces a series of signaling cascades and leads to activation of multiple transcription factors, including NF-kappaB. Although the mechanism of TCR-induced NF-kappaB activation is not fully understood, recent studies indicate that Bcl10 and CARMA1, two adaptor/scaffold proteins, play essential roles in mediating TCR-induced NF-kappaB activation. MALT1/paracaspase is a caspase-like protein that contains an N-terminal death domain, two Ig-like domains, and a C-terminal caspase-like domain. It binds to Bcl10 through its Ig-like domains and cooperates with Bcl10 to activate NF-kappaB. Recently, it has been shown that MALT1 is involved in mediating TCR signal transduction, leading to activation of NF-kappaB. In this study, we show that MALT1 is recruited into the lipid rafts of the immunological synapse following activation of the TCR and the CD28 coreceptor (CD3/CD28 costimulation). This recruitment of MALT1 is dependent on CARMA1 because CD3/CD28 costimulation failed to recruit MALT1 into lipid rafts in CARMA1-deficient T cells. In addition, we also found that MALT1 not only binds to Bcl10 directly, but also associates with CARMA1 in a Bcl10-independent manner. Therefore, MALT1, Bcl10, and CARMA1 form a trimolecular complex. Expression of a MALT1 deletion mutant containing only the N-terminal death domain and the two Ig-like domains completely blocked CD3/CD28 costimulation-induced, but not tumor necrosis factor-alpha-induced, NF-kappaB activation. Together, these results indicate that MALT1 is a crucial signaling component in the TCR signaling pathway.

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    • "TCR engagement induces the redistribution of BCL10 and MALT1 to the membrane rafts at the TCR complex, which is essential to activate NF-κB signalling [22], [23], [51]. Artificial membrane anchoring of MALT1 not only activated its protease activity and NF-κB signalling, but also induced MALT1 auto-proteolysis. "
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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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    • "HSC2 oral carcinoma cells, which marginally express MALT1, were obtained from the Cell Resource Center for Biomedical Research Institute of Development, Aging and Cancer (Tohoku University, Sendai, Japan). HSC2 cells stably expressing FLAG-tagged full-length wild-type MALT1 (wtMALT1HSC2 cells) and the NH2 terminal death and Ig-like domains-deleted dominant-negative MALT1 (ΔMALT1HSC2 cells; Che et al, 2004) and transfected vector alone (mockHSC2 cells) were established previously (Chiba et al, 2009). They were maintained in 10% fetal bovine serum and 100 units per ml of penicillin/streptomycin-containing DMEM (Sigma-Aldrich, St. Louis, MO, USA) in a conventional 5% CO2 incubator. "
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    ABSTRACT: Background: Expression of mucosa-associated lymphoid tissue 1 (MALT1) is inactivated in oral carcinoma patients with worse prognosis. However, the role in carcinoma progression is unknown. Unveiling genes under the control of MALT1 is necessary to understand the pathology of carcinomas. Methods: Gene data set differentially transcribed in MALT1-stably expressing and -marginally expressing oral carcinoma cells was profiled by the microarray analysis and subjected to the pathway analysis. Migratory abilities of cells in response to MALT1 were determined by wound-healing assay and time-lapse analysis. Results: Totally, 2933 genes upregulated or downregulated in MALT1-expressing cells were identified. The subsequent pathway analysis implicated the inhibition of epidermal growth factor and transforming growth factor-β signalling gene expression, and highlighted the involvement in the cellular movement. Wound closure was suppressed by wild-type MALT1 (66.4%) and accelerated by dominant-negative MALT1 (218.6%), and the velocities of cell migration were increased 0.2-fold and 3.0-fold by wild-type and dominant-negative MALT1, respectively. Conclusion: These observations demonstrate that MALT1 represses genes activating the aggressive phenotype of carcinoma cells, and suggest that MALT1 acts as a tumour suppressor and that the loss of expression stimulates oral carcinoma progression.
    British Journal of Cancer 06/2013; 109(1). DOI:10.1038/bjc.2013.307 · 4.82 Impact Factor
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    • "Early studies have shown that PKCθ recruitment to the IS is indirectly dependent on the PI3K interaction motif within the CD28 cytosolic tail (Harada et al., 2001). Thus, mutation of Met 173 within the mouse YMNM motif, which binds PI3K upon its tyrosine phosphorylation, resulted in decreased ability of CD28 to direct PKCθ recruitment to the cSMAC, and inhibited PKCθ-dependent activation of NF-κB to and the Il2 gene (Sanchez-Lockhart et al., 2004). "
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    ABSTRACT: Protein kinase C-theta (PKCθ) is a key enzyme in T lymphocytes, where it plays an important role in signal transduction downstream of the activated TCR and the CD28 costimulatory receptor. TCR/CD28 engagement triggers the translocation of the cytosolic PKCθ to the plasma membrane, where it localizes at the center of the immunological synapse (IS), which forms at the contact site between an antigen-specific T cell and antigen-presenting cells (APC). The cellular redistribution of PKCθ in resting versus activated T cells has been thoroughly investigated, but the mechanisms governing its translocation to the center of the IS, and how this unique localization relates to the biological activity of PKCθ have remained unclear until recently. A very recent study has shown that the unique V3 (hinge) domain of PKCθ is essential and sufficient for its localization at the IS, where it is anchored to the cytoplasmic tail of CD28 via an indirect mechanism, involving the Lck as an intermediate. Furthermore, the PKCθ-CD28 complex, which forms upon antigen stimulation, is localized at a newly recognized, TCRlow subregion of the central IS, where it forms an outer ring around the very center, TCRhigh subregion. Importantly, the association of PKCθ with CD28 is also essential for PKCθ-mediated activation of downstream signaling pathways, including the transcription factors NF-κB and NF-AT, which are sine qua non for the productive activation of T lymphocytes. Indeed, the use of V3-altered PKCθ mutants or the isolated V3 domain as a negative dominant mutant demonstrated that strategies, which disrupt the interaction between PKCθ and CD28, block T cell activation, proliferation and differentiation into pathogenic Th2 and Th17 (but not Th1) effector helper T cells. The recent progress made in understanding of the mechanism of recruitment and regulation of PKCθ activity at the IS is likely to facilitate the development of PKCθ-based therapeutic modalities for T cell-mediated diseases.
    Frontiers in Immunology 08/2012; 3:273. DOI:10.3389/fimmu.2012.00273
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