A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling

Joanne M. Hildebrand, Zhenghua Luo, Michelle K. Manske, Tammy Price-Troska, Steven C. Ziesmer, Wai Lin, Bruce S. Hostager, Susan L. Slager, Thomas E. Witzig, Stephen M. Ansell, James R. Cerhan, Gail A. Bishop, Anne J. Novak

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

The cytokine B cell activating factor (BAFF) and its receptor, BAFF receptor (BAFF-R), modulate signaling cascades critical for B cell development and survival. We identified a novel mutation in TNFRSF13C, the gene encoding human BAFF-R, that is present in both tumor and germline tissue from a subset of patients with non-Hodgkin lymphoma. This mutation encodes a His159Tyr substitution in the cytoplasmic tail of BAFF-R adjacent to the TRAF3 binding motif. Signaling through this mutant BAFF-R results in increased NF-κB1 and NF-κB2 activity and increased immunoglobulin production compared with the wild-type (WT) BAFF-R. This correlates with increased TRAF2, TRAF3, and TRAF6 recruitment to His159Tyr BAFF-R. In addition, we document a requirement for TRAF6 in WT BAFF-R signaling. Together, these data identify a novel lymphoma-associated mutation in human BAFF-R that results in NF-κB activation and reveals TRAF6 as a necessary component of normal BAFF-R signaling.

Original languageEnglish (US)
Pages (from-to)2569-2579
Number of pages11
JournalJournal of Experimental Medicine
Volume207
Issue number12
DOIs
StatePublished - Nov 22 2010

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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