Kinase-independent feedback of the TAK1/TAB1 complex on BCL10 proteolysis and NF-κB activation in lymphocytes (P1114)

Abstract

Abstract Somatic mutations resulting in constitutive activation of the CARMA1 scaffolding protein occur frequently in poor prognosis diffuse large B cell lymphoma (DLBCL). Such mutations directly promote assembly of the CARMA1, BCL10, MALT1 (CBM complex) thereby leading to activation of the IKK signalosome. These events lead to sustained NF-κB signaling, which is essential for lymphocyte survival. Thus, understanding the events that down-regulate CBM complex assembly is predicted to identify novel therapeutic targets in DLBCL. Notably, stimulation of antigen receptors simultaneously triggers both CARMA1-dependent BCL10 activation and CARMA-dependent-BCL10 degradation, which ultimately limits CARMA1 signaling. Using mutant B cell models, and genetic as well as biochemical approaches, we identify a kinase-independent requirement for the kinase, TAK1, and its adaptor, TAB1, in antigen receptor-induced BCL10 proteolysis. We show that TAK1 acts as an adaptor for E3 ubiquitin ligases that target BCL10 for degradation. Functionally, TAK1 over-expression restrains CARMA1-dependent NF-κB activation by reducing BCL10 levels. TAK1 also promotes counter-selection of NF-κB-addicted DLBCL lines by a dual mechanism involving kinase-independent degradation of BCL10 and kinase-dependent activation of JNK. Thus, by directly promoting BCL10 degradation, TAK1 counter-balances NF-κB and JNK signals essential for activation and survival of lymphocytes and CARMA1-addicted lymphoma types.