The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development.

Abstract

Tumor necrosis factor receptor-associated factor 3 (TRAF3) is an adaptor protein that inhibits signaling by CD40 and by the receptor for B cell-activating factor (BAFF) and negatively regulates homeostatic B cell survival. Loss-of-function mutations in TRAF3 are associated with human B cell malignancies, in particular multiple myeloma. The cytokine interleukin-6 (IL-6) supports the differentiation and survival of normal and neoplastic plasma cells. We found that mice with a deficiency in TRAF3 specifically in B cells (B-Traf3(-/-) mice) had about twice as many plasma cells as did their littermate controls. TRAF3-deficient B cells had enhanced responsiveness to IL-6, and genetic loss of IL-6 in B-Traf3(-/-) mice restored their plasma cell numbers to normal. TRAF3 inhibited IL-6 receptor (IL-6R)-mediated signaling by facilitating the association of PTPN22 (a nonreceptor protein tyrosine phosphatase) with the kinase Janus-activated kinase 1 (Jak1), which in turn blocked phosphorylation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Consistent with these results, the number of plasma cells in the PTPN22-deficient mice was increased compared to that in the wild-type mice. Our findings identify TRAF3 and PTPN22 as inhibitors of IL-6R signaling in B cells and reveal a previously uncharacterized role for TRAF3 in the regulation of plasma cell differentiation.

• Authors: Wai W Lin, Zuoan Yi, Laura L Stunz, Christian J Maine, Linda A Sherman, Gail A Bishop
• Journal: Science signaling (Sci Signal) Vol. 8 Issue 392 Pg. ra88 (Sep 01 2015) ISSN: 1937-9145 [Electronic] United States
• PMID: 26329582 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• IL6R protein, human
• Receptors, Interleukin-6
• TNF Receptor-Associated Factor 3
• TRAF3 protein, human
• PTPN22 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 22
• Ptpn22 protein, mouse

Topics

• Animals
• Humans
• Mice
• Mice, Knockout
• Plasma Cells (immunology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 22 (genetics, immunology)
• Receptors, Interleukin-6 (genetics, immunology)
• Signal Transduction (genetics, immunology)
• TNF Receptor-Associated Factor 3 (genetics, immunology)