A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling.
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.
Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
Joanne M
JM
Hildebrand
Zhenghua
Z
Luo
Michelle K
MK
Manske
Tammy
T
Price-Troska
Steven C
SC
Ziesmer
Wai
W
Lin
Bruce S
BS
Hostager
Susan L
SL
Slager
Thomas E
TE
Witzig
Stephen M
SM
Ansell
James R
JR
Cerhan
Gail A
GA
Bishop
Anne J
AJ
Novak
D000595:Amino Acid Sequence; D053265:B-Cell Activation Factor Receptor / Q000235:genetics*; D002460:Cell Line; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
D053265:B-Cell Activation Factor Receptor; D007136:Immunoglobulins; D016328:NF-kappa B; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; C435926:TNFRSF13C protein, human