Work

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

Year: 2015

Type: article

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.

Source: Science Signaling

DOI: 10.1126/scisignal.aaa5157

Authors: Wai W. Lin, Zuoan Yi, Laura L. Stunz, Christian J. Maine, Linda A. Sherman, Gail A. Bishop

Institutions: University of Iowa, Scripps Research Institute, Iowa City VA Medical Center

Language: English

Topic: Cytokine Signaling Pathways and Interactions

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green