From MALT lymphoma to the CBM signalosome: three decades of discovery

Abstract

The advent of molecular cytogenetics has led to the elucidation of genetic abnormalities that cause various congenital and oncological disorders. In B cell lymphoma, for example, a number of chromosomal translocations have been identified in and associated with the etiology of specific subtypes of lymphoma. Several recurrent chromosomal translocations have been identified in extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Cloning and characterization of the products of three mutually exclusive translocation breakpoints found in MALT lymphoma led to the discovery of a novel NF-κB-activating complex comprising the CARMA, Bcl10, and MALT1 proteins. This "CBM signalosome" acts downstream of the antigen receptors in lymphocytes as well as a number of non-lymphoid cell-surface receptors involved in a variety of biological processes. CBM signalosome activity is important for normal cellular functions and is perturbed in neoplastic and inflammatory disorders, making it a viable target for novel therapeutic design.

Figure 1

Overview of canonical and non-canonical NFκB activation. A number of different receptors, including TNFR1, TCR, IL-1R and GPCRs, can promote nuclear translocation of canonical NFκB heterodimers, which primarily comprise RelA and p50 (left). A number of different, receptor-specific, molecular mediators are involved in activation of NFκB, and the common steps that all NFκB-stimulating pathways must activate are depicted. These include activation of the IKK complex subunit IKKβ and subsequent phosphorylation, ubiquitination and degradation of IκBα, freeing sequestered canonical NFκB heterodimers and allowing them to translocate to the nucleus and drive transcription of responsive genes. In contrast to the multitude of canonical NFκB activators, only a limited number of stimuli are capable of activating non-canonical NFκB (right). Cognate ligand binding to members of the TNFR superfamily, including BAFF-R, CD40 and LT-βR, results in stabilization and activation of the critical kinase NIK, which then phosphorylates and activates another IKK complex subunit, IKKα. Activated IKKα then phosphorylates the inhibitory RelB-bound NFκB2 precursor, p100, targeting it for partial proteasomal processing to p52, which frees non-canonical RelB/p52 heterodimers to translocate to the nucleus and activate gene transcription. Stippled arrows represent events that have been omitted for simplicity.

Figure 2

The CARMA/Bcl10/MALT1 signalosome and the fusion oncoprotein API2-MALT1 activate canonical NFκB. (A) Schematic illustration of the structural domains in CBM components, wild-type API2 and API2-MALT1. The most commonly occurring API2-MALT1 fusion is depicted. (B) Activation of the antigen receptors and, presumably, stimulation of specific GPCRs promotes PKC activation and phosphorylation of the CARMA1/3 linker domain, which induces a conformational change and permits interaction with Bcl10 and MALT1. Oligomerized MALT1 interacts with the ubiquitin ligase TRAF6 and stimulates activation of the IKK complex, ultimately resulting in nuclear translocation of canonical NFκB heterodimers of RelA and p50. API2-MALT1 is able to auto-oligomerize, thereby supplanting the need for upstream activating stimuli.

Figure 3

MALT1 protease targets. The protein domain structure and amino acid sequences flanking the target arginines of the four known MALT1 protease sustrates, Bcl10, A20, CYLD and NIK, are depicted. (*) It should be noted that thus far, only API2-MALT1, and not wild-type MALT1, has been found to proteolytically cleave NIK.