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-B. Although the mechanism of TCR-induced NF-B activation is not fully understood, recent studies indicate that Bcl10 and CARMA1, two adaptor/scaffold proteins, play essential roles in mediating TCR-induced NF-B activation. MALT1/paracaspase is a caspase-like protein that contains an Nterminal 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-B. Recently, it has been shown that MALT1 is involved in mediating TCR signal transduction, leading to activation of NF-B. 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-␣-induced, NF-B activation. Together, these results indicate that MALT1 is a crucial signaling component in the TCR signaling pathway.T cell activation plays a critical role in regulation of the immune response. Dysregulation of this process results in cancer, autoimmunity, and immunodeficiency diseases. T cell activation is initiated by major histocompatibility complex molecules on antigen-presenting cells presenting antigen peptides to T cell receptors (TCRs) 1 on the surface of T cells. This stimulation of TCR-CD3 complexes induces a series of signal transduction events leading to activation of multiple transcription factors such as AP-1, NF-AT, and NF-B (1-3). However, stimulation of TCR/CD3 complexes alone is insufficient to activate T cells. Instead, this signal will induce T cell anergy or apoptosis. The complete activation of T cells requires a second "costimulatory" signal generated through interactions between B7-1(CD80)/B7-2(CD86) molecules on antigen-presenting cells and CD28 receptors on T cells. This combined stimulation of TCR/CD3 and CD28 molecules (known as CD3/CD28 costimulation) leads to optimal activation of multiple transcription factors, including NF-B, and subsequent production of interleukin-2 and other cytokines (4). The NF-B family of transcription factors plays a critical role in controlling expression of various cytokine and anti-apoptotic genes. NF-B activity is regulated through interactions with a series of cytoplasmic inhibitory proteins termed IB, which mask the nuclear localization signal of NF-B, thereby sequestering NF-B in the cytoplasm. Treatment of cells with various stim...

NF-κB signaling pathways regulated by CARMA family of scaffold proteins

“…Mutation of Ser109 to Ala residue in CARMA1 impairs its biological function [72]. Once activated, CARMA1 recruits the IKK complex [60,61] and other signaling molecules (Table 1) [63,[67][68][69]73], including Bcl10 and its pre-associated partner MALT1 [60,61,74]. TCR-induced formation of the CARMA1-Bcl10-MALT1 complex is critical for IKK activation.…”

The pathogenesis of MALT lymphomas: where do we stand?

“…Studies of knockout mice established an essential role for both BCL10 and MALT1 in transducing antigen-receptor signals to activate the NF-kB pathway. 30,38,39 Upon antigen stimulation, CARD11 (CARMA1/Bimp1) recruits BCL10 40 and MALT1 41 to the lipid rafts at the receptor, which is believed to induce the formation of BCL10/MALT1/TRAF6 oligomers. 42 This elicits the E3 ubiquitin ligase activity of the TRAF6 RING domain to synthesize a Lys63-linked polyubiquitin chain on TRAF6 itself and on IKKg, which also binds to CARD11.…”

CARMA3/Bcl10/MALT1-dependent NF-κB activation mediates angiotensin II-responsive inflammatory signaling in nonimmune cells

“…First, how does PKC, activated through ligation of the AT 1 R, communicate with CARMA3? In the lymphocyte, antigen stimulation leads to recruitment and clustering of PKC, CARMA1, Bcl10, MALT1, and even the IKK complex at localized, plasma membraneassociated signaling zones (32,(39)(40)(41)(42)(43). Thus, it is thought that signal-induced clustering of these factors plays an essential role in the transmission of information.…”