Essential Role of the Linear Ubiquitin Chain Assembly Complex in Lymphoma Revealed by Rare Germline Polymorphisms

Abstract

Constitutive activation of NF-κB is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), owing to upstream signals from the B cell receptor (BCR) and MyD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase γ, a necessary event in some pathways that engage NF-κB. Two germ line polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (~1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11/MALT1/BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RFN31-RBCK1 binding, decreased NF-κB and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target.

The paracaspase MALT1 cleaves the LUBAC subunit HOIL1 during antigen receptor signaling

“…This complex catalyzes linear ubiquitylation and participates in multiple signaling pathways converging on NF-κB (Iwai et al, 2014). Although the LUBAC is a central part of the CBM needed for IKK activation in lymphocytes and in ABC DLBCL cells, the exact role of HOIL1 remains elusive (Dubois et al, 2014;Yang et al, 2014). We now report that HOIL1 is a substrate of MALT1 that is cleaved in TCR-stimulated cells and in ABC DLBCL cells, and that this processing contributes to the optimal activation of NF-κB in lymphocytes.…”

“…We also provide evidence that exacerbated MALT1 activity in ABC DLBCL cells results in the constitutive cleavage of HOIL1. In addition to interfering with the LUBAC stability (Yang et al, 2014), targeting HOIL1 cleavage might therefore offer a new angle for therapeutic targeting in ABC DLBCL. How exactly HOIL1 exerts its negative function remains unclear.…”

“…This N-terminal fragment likely maintains the LUBAC activity and mediates aberrant NF-κB in ABC DLBCL (Dubois et al, 2014;Yang et al, 2014). HOIL1…”

Linear Polyubiquitination: A Crucial Regulator of NF-κB Activation

“…Recent analyses showed that LUBAC is essential for the growth of ABC DLBCL cells through suppression of NF-κB activity. Moreover, two rare SNPs in the HOIP gene are enriched in ABC DLBCL [ 21 ]. We have also observed that attenuation of LUBAC suppressed lung metastases of osteosarcomas in mice [ 22 ].…”

“…Aberrant NF-κB activation plays an essential role in the pathogenesis of activated B cell-like diffuse large B cell lymphomas (ABC DLBCL) [ 21 ]. Recent analyses showed that LUBAC is essential for the growth of ABC DLBCL cells through suppression of NF-κB activity.…”