Hypothetical model for the role of LUBAC in antigen receptor–induced NF-κB signaling. TCR and BCR stimulation by antigens triggers the activation of proximal adaptors and kinases, followed by the rapid assembly of a signaling platform (known as the CBM complex) that contains the scaffold proteins CARD11/BCL10 and the paracaspase MALT1. In ABC-DLBCL, the CBM complex is preassembled, which often results from somatic mutations in positive or negative regulatory signaling proteins. Formation of the CBM complex results in the downstream activation of the IKK complex, consisting of 2 kinases (IKKα and IKKβ) and an adaptor protein NEMO. IKK-mediated phosphorylation results in the nuclear translocation of NF-κB where it induces the expression of several genes that mediate T- and B-cell activation and proliferation. In ABC-DLBCL, NF-κB is constitutively activated leading to the expression of anti-apoptotic genes and cell survival. How CBM connects to the IKK complex is still largely unclear. Dubois et al demonstrate that TCR- and BCR-induced NF-κB signaling also involves a third multiprotein complex known as LUBAC (consisting of HOIP, HOIL-1, and SHARPIN). LUBAC is best known for its role in tumor necrosis factor–induced NF-κB signaling, where it modifies specific signaling proteins with head-to-tail linked (linear) ubiquitin modules. However, the study of Dubois et al shows a catalytic-independent role of LUBAC in lymphocytes. Their results are compatible with a model in which antigen receptor stimulation induces the formation of a large signalosome in which LUBAC functions as an adaptor between the CBM and IKK complexes.

Hypothetical model for the role of LUBAC in antigen receptor–induced NF-κB signaling. TCR and BCR stimulation by antigens triggers the activation of proximal adaptors and kinases, followed by the rapid assembly of a signaling platform (known as the CBM complex) that contains the scaffold proteins CARD11/BCL10 and the paracaspase MALT1. In ABC-DLBCL, the CBM complex is preassembled, which often results from somatic mutations in positive or negative regulatory signaling proteins. Formation of the CBM complex results in the downstream activation of the IKK complex, consisting of 2 kinases (IKKα and IKKβ) and an adaptor protein NEMO. IKK-mediated phosphorylation results in the nuclear translocation of NF-κB where it induces the expression of several genes that mediate T- and B-cell activation and proliferation. In ABC-DLBCL, NF-κB is constitutively activated leading to the expression of anti-apoptotic genes and cell survival. How CBM connects to the IKK complex is still largely unclear. Dubois et al demonstrate that TCR- and BCR-induced NF-κB signaling also involves a third multiprotein complex known as LUBAC (consisting of HOIP, HOIL-1, and SHARPIN). LUBAC is best known for its role in tumor necrosis factor–induced NF-κB signaling, where it modifies specific signaling proteins with head-to-tail linked (linear) ubiquitin modules. However, the study of Dubois et al shows a catalytic-independent role of LUBAC in lymphocytes. Their results are compatible with a model in which antigen receptor stimulation induces the formation of a large signalosome in which LUBAC functions as an adaptor between the CBM and IKK complexes.

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