Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival

Abstract

The CBM protein complex, consisting of the scaffold protein CARMA1, the adaptor protein BCL10 and the paracaspase enzyme MALT1, has a key role in transducing signals from the antigen receptors in T and B cells to the transcription factor NF-κB during lymphocyte activation. How this important protein complex is regulated has remained obscure but now Bidère et al. show that the CBM complex is regulated in two opposing ways by casein kinase 1α (CK1α), first promoting and then terminating receptor-induced NF-κB activity and lymphocyte activation. CK1α is also required for the constitutive NF-κB signalling found in lymphoma cells. This dual 'gating' function suggests that CK1α can act as a conditionally essential malignancy gene— potentially representing a new class of cancer therapeutic targets. The CBM complex has a key role in transducing signals from the antigen receptors in T and B cells to the transcription factor NF-κB during lymphocyte activation. Casein kinase 1α (CK1α) is shown to regulate the CBM complex in two opposing ways, first promoting and then subsequently terminating receptor-induced NF-κB activity and lymphocyte activation. The transcription factor NF-κB is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types1,2. Antigen receptor stimulation assembles an NF-κB activating platform containing the scaffold protein CARMA1 (also called CARD11), the adaptor BCL10 and the paracaspase MALT1 (the CBM complex), linked to the inhibitor of NF-κB kinase complex3,4,5,6,7,8,9,10,11,12, but signal transduction is not fully understood1. We conducted parallel screens involving a mass spectrometry analysis of CARMA1 binding partners and an RNA interference screen for growth inhibition of the CBM-dependent ‘activated B-cell-like’ (ABC) subtype of diffuse large B-cell lymphoma (DLBCL)12. Here we report that both screens identified casein kinase 1α (CK1α) as a bifunctional regulator of NF-κB. CK1α dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1α kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1α has thus a dual ‘gating’ function which first promotes and then terminates receptor-induced NF-κB. ABC DLBCL cells required CK1α for constitutive NF-κB activity, indicating that CK1α functions as a conditionally essential malignancy gene—a member of a new class of potential cancer therapeutic targets.