MALT1/Paracaspase Is a Signaling Component Downstream of CARMA1 and Mediates T Cell Receptor-induced NF-κB Activation
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.
- SourceAvailable from: Noah Isakov
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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). "
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 T cell antigen receptor (TCR) and the CD28 costimulatory receptor. Interest in PKCθ as a potential drug target has increased following recent findings that PKCθ is essential for harmful inflammatory responses mediated by Th2 (allergies) and Th17 (autoimmunity) cells as well as for graft-versus-host disease (GvHD) and allograft rejection, but is dispensable for beneficial responses such as antiviral immunity and graft-versus-leukemia (GvL) response. TCR/CD28 engagement triggers the translocation of the cytosolic PKCθ to the plasma membrane (PM), 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). However, the molecular basis for this unique localization, and whether it is required for its proper function have remained unresolved issues until recently. Our recent study resolved these questions by demonstrating that the unique V3 (hinge) domain of PKCθ and, more specifically, a proline-rich motif within this domain, 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 Lck protein tyrosine kinase (PTK) as an intermediate. Importantly, the association of PKCθ with CD28 is essential not only for IS localization, but also for PKCθ-mediated activation of downstream signaling pathways, including the transcription factors NF-κB and NF-AT, which are essential for productive T cell activation. Hence, interference with formation of the PKCθ-Lck-CD28 complex provides a promising basis for the design of novel, clinically useful allosteric PKCθ inhibitors. An additional recent study demonstrated that TCR triggering activates the germinal center kinase (GSK)-like kinase (GLK) and induces its association with the SLP-76 adaptor at the IS, where GLK phosphorylates the activation loop of PKCθ, converting it into an active enzyme. This recent progress, coupled with the need to study the biology of PKCθ in human T cells, 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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- "The antigen-induced signaling pathways for T cell activation through the T cell receptor (TCR) and co-stimulatory molecule CD28 have been extensively characterized. The binding of antigen peptide on MHC induces the clustering of a receptor complex that includes several tyrosine phosphorylated proteins , which recruits downstream signaling molecules including PKCh, CARMA1, Bcl10, and MALT1 to stimulate the activation of IKK     . In addition, the clustering of TCR results in the activation of all of the three MAPK pathways (ERK, JNK, p38) leading to AP-1, which have been identified as critical pathways regulating IL-2 production [16–21]. "
ABSTRACT: We focused on the functional involvement of transforming growth factor-beta-activated kinase 1 (TAK1) in transcriptional regulation of interleukin-2 (IL-2) in T cells. Costimulation of Jurkat cells with 12-O-tetradecanoylphorbol-13-acetate and A23187 leads to a rapid phosphorylation of TAK1 and TAK1-binding protein 1 (TAB1), critical for TAK1 activation. A specific inhibitor of TAK1 blocked production of IL-2. In addition, overexpression of TAK1 and TAB1 induced secretion of IL-2. CD28-responsive element/activator protein-1-binding site (RE/AP) within the IL-2 promoter was a functional target for TAK1. The RE/AP-driven transcription was regulated by TAK1-mediated activation of the c-Jun NH2-terminal kinase, p38 and IkappaB kinase. These results indicate that TAK1 plays a critical role in T cell activation by controlling production of IL-2.FEBS Letters 01/2006; 579(29):6641-6. DOI:10.1016/j.febslet.2005.10.059 · 3.34 Impact Factor
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- "Although Ser565 does not fall into a putative PKC phosphorylation site, we also generated S565A mutant of CARMA1 and found that this mutant is also defective for TCR-induced NF-kB activation (Table 1), which further suggests the importance of this region for CARMA1's function. Previous studies indicate that CARMA1 recruits downstream signaling components such as Bcl10, IKK, and MALT1 into lipid rafts after CD3-CD28 costimulation (Che et al., 2004; Gaide et al., 2002; Hara et al., 2004; Figure 3. CARMA3, but Not CARMA2, Can Rescue TCR-Induced NF-kB Activation in CARMA1-Deficient Jurkat T Cells (A) Structural domain of CARMA family members. (B) Sequence aliments of the Linker region of CARMA1, CARMA2, and CARMA3. "
ABSTRACT: CARMA1 mediates T cell receptor (TCR)-induced NF-kappaB activation. However, how TCR links to CARMA1 in the signaling pathway is not clear. Here, we show that CARMA1 is inducibly phosphorylated after TCR-CD28 costimulation. This phosphorylation is likely induced by PKCtheta, since PKCtheta induces phosphorylation of CARMA1 in vitro and in vivo. Our results indicate that the PKCtheta-induced phosphorylation of CARMA1 likely occurs on Ser552 on the Linker region of CARMA1. Importantly, expression of CARMA1 mutant, in which Ser552 is mutated, fails to mediate TCR-induced NF-kappaB activation in CARMA1-deficient T cells. The functional defect of this CARMA1 mutant is likely due to the fact that this mutant cannot be phosphorylated at the critical residue, thereby failing to recruit the downstream signaling components into the immunological synapse. Together, our studies provide the first genetic evidence that the phosphorylation of CARMA1 plays a critical role in the TCR signaling pathway.Immunity 01/2006; 23(6):575-85. DOI:10.1016/j.immuni.2005.10.007 · 19.75 Impact Factor