TRAF Proteins in CD40 Signaling

Abstract

The tumor necrosis factor receptor (TNFR) superfamily molecule CD40 is expressed by a wide variety of cell types following activation signals, and constitutively on B lymphocytes, macrophages, and dendritic cells. CD40 signals to cells stimulate kinase activation, gene expression, production of a antibody and a variety of cytokines, expression or upregulation of surface molecules, and protection or promotion of apoptosis. Initial steps in CD40-mediated signal cascades involve the interactions of CD40 with various members of the TNFR-associated factor (TRAF) family of cytoplasmic proteins. This review summarizes current understanding of the nature of these interactions, and how they induce and regulate CD40 functions.

Roles of TRAF molecules in B lymphocyte function

“…In 1994, TRAF3 became the first cytoplasmic molecule demonstrated to associate with CD40 (reviewed in [2]). However, for many years, its roles in CD40 signaling were largely unknown, and are still not completely understood.…”

“…TRAF2 was initially demonstrated to bind CD40 by exogenous overexpression studies in adenocarcinoma cell lines, in which it promotes JNK activation and the activity of NF-κB reporter genes (reviewed in [2]. Because TRAF2 -/-mice have an early lethal phenotype [8], they could not provide clear information on the roles played by TRAF2 in CD40 signaling to B cells.…”

“…TRAF6 directly binds CD40 via a membrane-proximal site distinct from the overlapping site used by other TRAFs [2], but recent evidence indicates that TRAF6 can also regulate CD40-induced JNK activation in B cells without binding to CD40 [16]. CD40 mutants that cannot bind TRAF6 show defects in B cell-mediated IL-6 production [17], and if expressed in TRAF2 -/-B cell lines, cannot activate canonical NF-κB activation or CD80 upregulation [11].…”

“…B cell CD40 is important in the induction of B cell survival and expansion, immunoglobulin (Ig) production and isotype switching, upregulation of surface molecules involved in B cell antigen presentation, differentiation to B memory cells, and the production of various cytokines (reviewed in [1]. The TRAF molecules have been shown to contribute to each of these functions (reviewed in [2].In 1994, TRAF3 became the first cytoplasmic molecule demonstrated to associate with CD40 (reviewed in [2]). However, for many years, its roles in CD40 signaling were largely unknown, and are still not completely understood.…”

“…Recently, mice made conditionally deficient in TRAF3 only in CD19+ B cells show no deficiencies in CD40 signaling in vitro and have enhanced antibody responses [7]. TRAF2 was initially demonstrated to bind CD40 by exogenous overexpression studies in adenocarcinoma cell lines, in which it promotes JNK activation and the activity of NF-κB reporter genes (reviewed in [2]. Because TRAF2 -/-mice have an early lethal phenotype [8],…”