A catalytic-independent role for the LUBAC in NF-κB activation upon antigen receptor engagement and in lymphoma cells.
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.
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 1014, Hôpital Paul Brousse, Villejuif, France;
Sonia M
SM
Dubois
Catherine
C
Alexia
Youtong
Y
Wu
Héloïse M
HM
Leclair
Claire
C
Leveau
Emilie
E
Schol
Thierry
T
Fest
Karin
K
Tarte
Zhijian J
ZJ
Chen
Julie
J
Gavard
Nicolas
N
Bidère
D002384:Catalysis; D045744:Cell Line, Tumor; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000502:physiology; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D025801:Ubiquitin