Mechanisms of TRAF3 Regulation of TLR Signaling in B Lymphocytes

Abstract

Abstract TRAF3 is an adaptor protein that binds to receptors of the TNFR superfamily and exerts multiple regulatory functions in signaling pathways. However, functions are cell type and context dependent. B cell TRAF3 inhibits homeostatic NFκB2 activation, CD40/BAFFR signaling and other pro-survival signaling pathways; restraint of survival is a B cell unique TRAF3 function. Loss of function mutations of human TRAF3 are detected in B cell lymphoma and multiple myeloma. In addition to homeostatic survival, we found that TRAF3 inhibits B cell TLR signaling, a pathway implicated in B cell lymphomagenesis and autoimmunity. Numerous reports describe TLR function in myeloid cells, but specific TLR signaling pathways in B cells are under-studied. B cell TRAF3 inhibits TLR-mediated cytokine and Ab production, and Ig class switching. Our <underline>working hypothesis</underline> is that B cell TRAF3 regulates the expression, recruitment and/or post-translational modification of TLR signaling proteins. Preliminary data show that B cell TRAF3 associates with signaling proteins MyD88 and IRAK1, and the kinase Syk following TLR stimulation. We are currently investigating how this association normally restrains the functions of these proteins in promoting TLR signals to B cells. We expect that information gained will provide new insights into the molecular mechanisms contributing to the regulation of B cells by TRAF3 in TLR signaling, potentially informing selection and development of more targeted therapies for B cell malignancies and autoimmunity.