title: Differential regulation of CD40-mediated TNF receptor-associated factor degradation in B lymphocytes.
abstract: Engagement of CD40 on murine B cells by its ligand CD154 induces the binding of TNFR-associated factors (TRAFs) 1, 2, 3, and 6, followed by the rapid degradation of TRAFs 2 and 3. TRAF degradation occurs in response to signaling by other TNFR superfamily members, and is likely to be a normal regulatory component of signaling by this receptor family. In this study, we found that receptor-induced TRAF degradation limits TRAF2-dependent CD40 signals to murine B cells. However, TRAFs 1 and 6 are not degraded in response to CD40 engagement, despite their association with CD40. To better understand the mechanisms underlying differential TRAF degradation, mixed protein domain TRAF chimeras were analyzed in murine B cells. Chimeras containing the TRAF2 zinc (Zn) domains induced effective degradation, if attached to a TRAF domain that binds to the PXQXT motif of CD40. However, the Zn domains of TRAF3 and TRAF6 could not induce degradation in response to CD40, regardless of the TRAF domains to which they were attached. Our data indicate that TRAF2 serves as the master regulator of TRAF degradation in response to CD40 signaling, and this function is dependent upon both the TRAF Zn domains and receptor binding position.
authors.affiliation: Interdisciplinary Graduate Program in Immunology, Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: Carissa R
authors.initials: CR
authors.lastname: Moore
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D001665:Binding Sites; D019013:CD40 Antigens / Q000378:metabolism*; D002460:Cell Line; D051379:Mice; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*; D015032:Zinc
chemical_list: D019013:CD40 Antigens; D011993:Recombinant Fusion Proteins; D047992:TNF Receptor-Associated Factor 2; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D015032:Zinc