Key Points• LUBAC elements HOIP and SHARPIN participate in T-cell receptor-mediated NF-kB activation independently of HOIP catalytic activity.• LUBAC silencing compromises constitutive NF-kB activation and cell survival in ABC DLBCL lines.Antigen receptor-mediated nuclear factor kB (NF-kB) activation relies on the formation of a large multi-protein complex that contains CARMA1, BCL10, and MALT1 (CBM complex). This signalosome is pirated in the activated B-cell-like subgroup of diffuse large B-cell lymphoma (ABC DLBCL) to drive aberrant NF-kB activation, thereby promoting cell survival and propagation. Using an unbiased proteomic approach, we screened for additional components of the CBM in lymphocytes. We found that the linear ubiquitin chain assembly complex (LUBAC), which was previously linked to cytokine-mediated NF-kB activation, dynamically integrates the CBM and marshals NF-kB optimal activation following antigen receptor ligation independently of its catalytic activity. The LUBAC also participates in preassembled CBM complex in cells derived from ABC DLBCL. Silencing the LUBAC reduced NF-kB activation and was toxic in ABC DLBCL cell lines. Thus, our findings reveal a role for the LUBAC during lymphocyte activation and in B-cell malignancy. (Blood. 2014;123(14):2199-2203) IntroductionThe activated B-cell like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) constitutes the most aggressive DLBCL entity. 1 In contrast to germinal center B-cell-like (GCB) subtype of DLBCL, ABC DLBCL survival and proliferation require the constitutive activation of nuclear factor kB (NF-kB) transcription factors, which often results from somatic mutations in CD79B, CARD11 (also called CARMA1), MYD88, and TNFAIP3 genes.2 New perspectives for treatments restricted to the lymphoid compartment came from genomic-scale RNA interference screens, which unveiled that ABC DLBCL exploited a multi-protein complex that contains CARMA1, BCL10, and MALT1 (CBM complex) normally engaged in conveying NF-kB following antigen receptor engagement. [3][4][5][6] Within the CBM, Lys-63 (K63)-linked ubiquitylation of BCL10 and MALT1 ensures the recruitment and activation of the inhibitor of NF-kB kinase (IKK, composed of IKKa, IKKb, and NEMO) through IKKb phosphorylation and NEMO poly-ubiquitylation.7-9 IKK subsequently authorizes NF-kB to shuttle in the nucleus and exert its transcriptional activity by phosphorylating its cognate inhibitors (IkBs), which further undergo proteasomal degradation. Here, we screened for additional CBM partners and identified the linear ubiquitin chain assembly complex (LUBAC), which comprises 2 E3 ligases, HOIL-1 and HOIP, and SHARPIN. 11Although this tripartite complex was previously linked to cytokine-, bacteria-, and genotoxic stress-mediated NF-kB signaling, 12-17 its involvement in adaptive immunity remains unknown. We now show that the LUBAC binds to the CBM and governs NF-kB activation upon antigen receptor engagement independently of HOIP catalytic activity. In ABC DLBCL cells, the LUBAC is integral to pre...