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The oncogenic membrane protein LMP1 sequesters TRAF3 in B-cell lymphoma cells to produce functional TRAF3 deficiency

Pradeep Bangalore-Prakash, Laura L. Stunz, Nurbek Mambetsariev, Amy L. Whillock, Bruce S. Hostager and Gail A. Bishop

Key Points

  • Expression of the Epstein-Barr virus–encoded oncoprotein LMP1 leads to sequestration of TRAF3 in B-lymphoma cells.

  • This sequestration inhibits TRAF3-negative regulation of prosurvival membrane, cytoplasmic, and nuclear signaling events in the B cell.

Abstract

Loss-of-function mutations in genes encoding the signaling protein tumor necrosis factor receptor–associated factor 3 (TRAF3) are commonly found in human B-cell malignancies, especially multiple myeloma and B-cell lymphoma (BCL). B-cell TRAF3 deficiency results in enhanced cell survival, elevated activation receptor signaling, and increased activity of certain transcriptional pathways regulating expression of prosurvival proteins. A recent analysis of TRAF3 protein staining of ∼300 human BCL tissue samples revealed that a higher proportion of samples expressing the oncogenic Epstein-Barr virus–encoded protein latent membrane protein 1 (LMP1) showed low/negative TRAF3 staining than predicted. LMP1, a dysregulated mimic of the CD40 receptor, binds TRAF3 more effectively than CD40. We hypothesized that LMP1 may sequester TRAF3, reducing its availability to inhibit prosurvival signaling pathways in the B cell. This hypothesis was addressed via 2 complementary approaches: (1) comparison of TRAF3-regulated activation and survival-related events with relative LMP1 expression in human BCL lines and (2) analysis of the impact upon such events in matched pairs of mouse BCL lines, both parental cells and subclones transfected with inducible LMP1, either wild-type LMP1 or a mutant LMP1 with defective TRAF3 binding. Results from both approaches showed that LMP1-expressing B cells display a phenotype highly similar to that of B cells lacking TRAF3 genes, indicating that LMP1 can render B cells functionally TRAF3 deficient without TRAF3 gene mutations, a finding of significant relevance to selecting pathway-targeted therapies for B-cell malignancies.

  • Submitted June 22, 2017.
  • Accepted November 16, 2017.
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