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

Journal of Experimental Medicine - Tập 207 Số 12 - Trang 2569-2579 - 2010
Joanne M. Hildebrand1,2,3, Zhenghua Luo1,4,3, Michelle K. Manske1,4,3, Tammy Price-Troska1,4,3, Steven C. Ziesmer1,4,3, Wai Lin1,4,3, Bruce S. Hostager1,4,3, Susan L. Slager5,6,7, Thomas E. Witzig5,6,7, Stephen M. Ansell5,6,7, James R. Cerhan5,6,7, Gail A. Bishop1,8,4,3, Anne J. Novak5,6,7
1Department of Internal Medicine 1 , 2 , and 3
2Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
3the Veterans Affairs Medical Center, University of Iowa, Iowa City, IA 52242 1 , 2 , and 3
4Department of Microbiology, Department of Internal Medicine, and the Veterans Affairs Medical Center, University of Iowa, Iowa City, IA 52242
5Division of Biomedical Statistics and Informatics 4 , 5 , and 6
6Division of Epidemiology, Mayo Clinic, Rochester, MN 55905 4 , 5 , and 6
7Division of Hematology, Division of Biomedical Statistics and Informatics, and Division of Epidemiology, Mayo Clinic, Rochester, MN 55905
8Department of Microbiology 1 , 2 , and 3

Tóm tắt

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.

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