Search

• The CBM signaling complex mediates T-cell and B-cell receptor-dependent lymphocyte activation. • Insights provided by 3D structures of CBM protein-protein interactions are highlighted in this review. • In the CBM supramolecular filamentous complex, CARMA1 acts as the nucleator to promote BCL10 polymerization and MALT1 activation. • BCL10 recruitment to CARMA1 and BCL10 oligomerization are interconnected processes that are dependent on one another. • CBM complex formation facilitates dimerization of the MALT1 paracaspase domain which leads to MALT1 protease activation. The CBM complex, which is composed of the proteins CARMA1, BCL10, and MALT1, serves multiple pivotal roles as a mediator of T -cell receptor and B-cell receptor-dependent NF-κB induction and lymphocyte activation. CARMA1, BCL10, and MALT1 are each proto-oncoproteins and dysregulation of CBM signaling, as a result of somatic gain-of-function mutation or chromosomal translocation, is a hallmark of multiple lymphoid malignancies including Activated B-cell Diffuse Large B-cell Lymphoma. Moreover, loss-of-function as well as gain-of-function germline mutations in CBM complex proteins have been associated with a range of immune dysregulation syndromes. A wealth of detailed structural information has become available over the past decade through meticulous interrogation of the interactions between CBM components. Here, we review key findings regarding the biochemical nature of these protein-protein interactions which have ultimately led the field to a sophisticated understanding of how these proteins assemble into high-order filamentous CBM complexes. To date, approaches to therapeutic inhibition of the CBM complex for the treatment of lymphoid malignancy and/or auto-immunity have focused on blocking MALT1 protease function. We also review key studies relating to the structural impact of MALT1 protease inhibitors on key protein-protein interactions. [ABSTRACT FROM AUTHOR]