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

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/CARD11, the adaptor BCL10, and the paracaspase MALT1 (CBM complex), linked to the inhibitor of NF-κB kinase (IKK) complex3–12, but signal transduction is not fully understood1. We conducted parallel screens involving a mass spectrometry analysis of CARMA1 binding partners and an RNAi 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 upon T cell receptor (TCR) engagement to augment cytokine production and lymphocyte proliferation. However, CK1α kinase activity plays a counterposing 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” (CEMal) gene - a member of a new class of potential cancer therapeutic targets

Multifunctional roles for MALT1 in T-cell activation

The activation of T cells is vital to the successful elimination of pathogens, but can also have a deleterious role in autoimmunity and transplant rejection. Various signalling pathways are triggered by the T-cell receptor; these have key roles in the control of the T-cell response and represent interesting targets for therapeutic immunomodulation. Recent findings define MALT1 (mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1) as a protein with proteolytic activity that controls T-cell activation by regulating key molecules in T-cell-receptor-induced signalling pathway