Antigen receptor signaling to NF-kappaB via CARMA1, BCL10, and MALT1

Abstract

The signaling pathway controlling antigen receptor-induced regulation of the transcription factor NF-kappaB plays a key role in lymphocyte activation and development and the generation of lymphomas. Work of the past decade has led to dramatic progress in the identification and characterization of new players in the pathway. Moreover, novel enzymatic activities relevant for this pathway have been discovered, which represent interesting drug targets for immuno-suppression or lymphoma treatment. Here, we summarize these findings and give an outlook on interesting open issues that need to be addressed in the future.

Figure 1.

Molecular structure of CARMA1, BCL10, and MALT1. CARMA1 has an amino-terminal caspase-recruitment domain (CARD) that is followed by a coiled coil domain and a linker region. The carboxy-terminal region of CARMA1 contains a PDZ domain (a motif present in the Psd-95, Dlg and ZO-1 proteins), a Src homology-3 (SH3) domain and a guanylate kinase (GUK) motif characteristic of proteins of the membrane-associated guanylate kinase (MAGUK) family (Thome and Tschopp 2003). BCL10 harbors an amino-terminal CARD motif and a carboxy-terminal extension of unknown structure. The carboxy-terminal part of the BCL10 CARD and a short stretch of 13 amino acids following the CARD are required for constitutive binding to MALT1 (Lucas et al. 2001; Langel et al. 2008). MALT1 contains an amino-terminal death domain (DD) that is followed by two immunoglobulin (Ig)-like domains required for BCL10 binding (Lucas et al. 2001). The carboxy-terminal part of MALT1 contains the protease domain, a third Ig domain, and an extension of unknown structure (Uren et al. 2000).

Figure 2.

Phosphorylation events affecting CARMA1 function. (A) In resting cells, CARMA1 adopts an inactive conformation that is stabilized by an intramolecular interaction between the CARD and the linker region. Antigen receptor stimulation triggers the phosphorylation of the CARMA1 linker motif and the region between the CARD and coiled coil motifs. This is thought to induce a conformational change, possibly by electrostatic repulsion, which unfolds the CARMA1 conformation, allowing the CARD to bind to the CARD motif of BCL10. (B) Summary of proposed phosphorylation events proposed to positively or negatively regulate CARMA1 function. See Table 1 and text for further details.

Figure 3.

Overview of the multiple functions of BCL10 and its binding partners. (A) T-cell receptor (TCR) triggering leads to the rapid phosphorylation of BCL10, which is likely to control TCR-induced actin polymerization in a CARMA1- and MALT1-independent manner. (B) TCR/CD28 costimulation induces formation of the CBM complex, which controls IKK mediated NF-κB activation by promoting the activation of the IKK complex. Within this complex, MALT1-bound TRAF6 is thought to mediate K63-linked ubiquitination of BCL10 and MALT1, promoting recruitment of the IKK complex via the ubiquitin-binding IKKγ subunit. Additionally, TRAF6-mediated ubiquitination of IKKγ may contribute to IKK activation. (C) CBM complex formation is required for the activation of MALT1 protease function. BCL10 serves as a substrate of MALT1; its cleavage may regulate β1 integrin-mediated T-cell adhesion.

Figure 4.

Proposed model for MALT1 function in NF-κB activation. B-cell receptor (BCR) stimulation induces formation of the CBM complex, which controls NF-κB activation through at least two different mechanisms. The scaffold function of BCL10 and MALT1 are required for TRAF6 recruitment and ubiquitination-dependent activation of the IKK complex, which phosphorylates IκB proteins. The protease activity of MALT1 also contributes to NF-κB activation in an IKK-independent manner, through cleavage of an unknown substrate (???). This might control IκBβ degradation, which occurs with slower kinetics than IκBα degradation and is sustained (Whiteside and Israel 1997), possibly because it depends on additional signaling events. Alternatively, MALT1 protease activity might control NF-κB1 activation at the level of its nuclear translocation or transcriptional activity. The presence of oncogenic mutations in CARMA1 or its upstream regulators may render this pathway constitutively active in diffuse large B-cell lymphoma of the activated B-cell type (ABC DLBCL) (see text for details).