An Atypical Tumor Necrosis Factor (TNF) Receptor-associated Factor-binding Motif of B Cell-activating Factor Belonging to the TNF Family (BAFF) Receptor Mediates Induction of the Noncanonical NF-κB Signaling Pathway

Abstract

BAFF receptor (BAFFR) is a member of the TNF receptor (TNFR) superfamily that regulates the survival and maturation of B cells. BAFFR exerts its signaling function by inducing activation of NF-B, although the underlying mechanism has not been well defined. By using a chimeric BAFFR, we show that BAFFR preferentially induces the noncanonical NF-B signaling pathway. This specific function of BAFFR is mediated by a sequence motif, PVPAT, which is homologous to the TRAF-binding site (PVQET) present in CD40, a TNFR known to induce both the canonical and noncanonical NF-B pathways. Mutation of this putative TRAF-binding motif within BAFFR abolishes its interaction with TRAF3 as well as its ability to induce noncanonical NF-B. Interestingly, modification of the PVPAT sequence to the typical TRAF-binding sequence, PVQET, is sufficient to render the BAFFR capable of inducing strong canonical NF-B signaling. Further, this functional acquisition of the modified BAFFR is associated with its stronger and more rapid association with TRAF3. These findings suggest that the PVPAT sequence of BAFFR not only functions as a key signaling motif of BAFFR but also determines its signaling specificity in the induction of the noncanonical NF-B pathway.

Non-canonical NF-κB signaling pathway

“…BAFFR differs from many other TNFR superfamily members in that it predominantly activates the non-canonical NF-κB signaling pathway with only weak activity in the induction of canonical NF-κB pathway [11,49]. This unique feature of BAFFR is primarily due to its possession of an atypical TRAF-binding sequence, which interacts with TRAF3 but not with TRAF2 [49]. Thus, BAFFR crosslinking triggers degradation of TRAF3, but not TRAF2, as opposed to the degradation of both TRAFs by many other TNFRs.…”

“…However, recruitment of TRAF2 is required for activation of the canonical NF-κB pathway. Indeed, a two-amino-acid substitution that converts this atypical TRAF-binding motif of BAFFR to a typical TRAF-binding motif renders BAFFR competent in binding TRAF2 and inducing canonical NF-κB activation [49]. BAFFR-mediated induction of p100 processing contributes to the survival of transitional and mature B cells, probably through induction of anti-apoptotic genes like bcl-2 and bcl-x [11].…”

“…A study using BAFFR and CD40 suggests that recruitment of these TRAF members to the receptor complex is essential for their degradation [49]. CD40 contains a typical TRAF-binding motif capable of recruiting both TRAF2 and TRAF3, whereas BAFFR contains an atypical TRAF-binding motif that selectively recruits TRAF3.…”

“…Consequently, ligation of CD40 leads to degradation of both TRAF2 and TRAF3, whereas ligation of BAFFR leads to degradation of only TRAF3. A two-amino-acid substitution to convert the atypical TRAF-binding motif of BAFFR to a typical TRAF-binding motif renders the modified BAFFR capable of recruiting and degrading both TRAF2 and TRAF3 [49]. More recent studies reveal that the inducible degradation of TRAF2 and TRAF3 is mediated through their ubiquitination by cIAP1 and cIAP2 [66].…”

Defining a transcriptional fingerprint of murine splenic B-cell development

“…[24][25][26][27] BAFF binding to its receptor, BAFF-R, induces activation of an alternative NF-kB signaling pathway (utilizing p52 homodimers) [28][29][30][31] and downregulates the pro-apoptotic protein Bim through a heightened activation of extracellular signal-regulated kinase. 32 Animals deficient in BAFF or BAFF-R show a profound loss in peripheral mature B-cell populations, but B-cell development in the marrow and the migration of T1 B cells into the spleen are not altered.…”