Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms.

Abstract

UNLABELLED:

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 germline 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 RNF31-RBCK1 binding, decreased NF-κB activation, and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target.

SIGNIFICANCE:

We provide genetic, biochemical, and functional evidence that the LUBAC ubiquitin ligase is a therapeutic target in ABC DLBCL, the DLBCL subtype that is most refractory to current therapy. More generally, our findings highlight the role of rare germline-encoded protein variants in cancer pathogenesis.

• Authors: Yibin Yang, Roland Schmitz, Joseph Mitala, Amanda Whiting, Wenming Xiao, Michele Ceribelli, George W Wright, Hong Zhao, Yandan Yang, Weihong Xu, Andreas Rosenwald, German Ott, Randy D Gascoyne, Joseph M Connors, Lisa M Rimsza, Elias Campo, Elaine S Jaffe, Jan Delabie, Erlend B Smeland, Rita M Braziel, Raymond R Tubbs, James R Cook, Dennis D Weisenburger, Wing C Chan, Adrian Wiestner, Michael J Kruhlak, Kazuhiro Iwai, Federico Bernal, Louis M Staudt
• Journal: Cancer discovery (Cancer Discov) Vol. 4 Issue 4 Pg. 480-93 (Apr 2014) ISSN: 2159-8290 [Electronic] United States
• PMID: 24491438 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Peptides
• Transcription Factors
• RBCK1 protein, human
• RNF31 protein, human
• Ubiquitin-Protein Ligases
• Protein Serine-Threonine Kinases
• NF-kappa B kinase

Topics

• Binding Sites
• Cell Line, Tumor
• Circular Dichroism
• Genetic Variation
• Germ-Line Mutation
• Humans
• Lymphoma, Large B-Cell, Diffuse (genetics, pathology)
• Models, Molecular
• Peptides (chemical synthesis, pharmacology)
• Polymorphism, Single Nucleotide
• Protein Serine-Threonine Kinases (metabolism)
• Protein Structure, Secondary
• Transcription Factors (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)