A catalytic-independent role for the LUBAC in NF-κB activation upon antigen receptor engagement and in lymphoma cells

• Published in: Blood 2014-04, Vol.123 (14), p.2199-2203
• Main Authors: Dubois, Sonia M., Alexia, Catherine, Wu, Youtong, Leclair, Héloïse M., Leveau, Claire, Schol, Emilie, Fest, Thierry, Tarte, Karin, Chen, Zhijian J., Gavard, Julie, Bidère, Nicolas
• Format: Article
• Language: English
• Subjects: Catalysis; Cell Line, Tumor; Humans; Jurkat Cells; Life Sciences; Lymphocyte Activation - physiology; Lymphoma - metabolism; Lymphoma - pathology; NF-kappa B - chemistry; NF-kappa B - metabolism; Protein Binding; Protein Interaction Domains and Motifs - physiology; Receptors, Antigen, T-Cell - metabolism; Ubiquitin - metabolism; Ubiquitination - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-05-504019

Antigen receptor-mediated nuclear factor κB (NF-κB) 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-κB 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-κB activation, dynamically integrates the CBM and marshals NF-κB 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-κB 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. •LUBAC elements HOIP and SHARPIN participate in T-cell receptor-mediated NF-κB activation independently of HOIP catalytic activity.•LUBAC silencing compromises constitutive NF-κB activation and cell survival in ABC DLBCL lines.