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

Science Signaling
Wai W LinGail A Bishop

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 identif...Continue Reading

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Citations

Apr 14, 2016·Trends in Molecular Medicine·Gökhan CildirVinay Tergaonkar
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Apr 19, 2021·Seminars in Arthritis and Rheumatism·Kalthoum TizaouiAndreas Kronbichler
Aug 22, 2021·The Journal of Biological Chemistry·Hanzeng LiGail A Bishop

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