API2-MALT1 oncoprotein promotes lymphomagenesis via unique program of substrate ubiquitination and proteolysis

Core Tip

Core tip: We summarize the identification of novel API2-mucosa-associated lymphoid tissue (MALT) 1-interacting proteins that uniquely mediate the cellular effects of the fusion oncoprotein but not wild-type API2 or MALT1. API2-MALT1 recruits receptor interacting protein 1 and tumor necrosis factor (TNF) receptor associated factor 2, which normally function downstream of the TNF receptor, and utilizes these proteins to communicate unregulated canonical nuclear factor-κB (NF-κB) in a manner that does not depend on the protease activity of MALT1. Simultaneously, NF-κB inducing kinase is recruited to API2-MALT1 and is proteolytically cleaved by the MALT1 protease domain to generate a stable, non-canonical NF-κB-activating fragment. Finally, LIM domain and actin-binding protein 1 is similarly recruited and cleaved as an API2-MALT1 specific target and its cleavage mediates an NF-κB-independent mechanism of oncogenesis. Additional factors, including SMAC and BCL10, may also play key roles as API2-MALT1 binding partners and downstream signaling factors. Thus, the API2-MALT1 fusion utilizes a distinct set of protein-protein interactions to leverage multiple, divergent mechanisms and achieve potent oncogenic reprogramming of affected B cells.