title: TRAF2 and p38 are involved in B cells CD40-mediated APE/Ref-1 nuclear translocation: a novel pathway in B cell activation.
abstract: The interaction between CD40 and its ligand CD40L plays a key role in the regulation of B cell proliferation, activation, isotype switching and the humoral memory response. APE/Ref-1 plays a key role in transcriptional responses during CD40-mediated B cell activation. It is demonstrated that CD40 signaling is mediated principally through TRAF adapter proteins. Different TRAFs exhibit specific biological functions and the role of individual TRAFs in the activation of different CD40-dependent signaling pathways has not yet been defined. To better understand the role of these factors in CD40-mediated B cell activation and how they contribute to APE/Ref-1 activity, we investigated the TRAF molecules and the downstream protein kinases directly activated in the pathways triggered by CD40. Here we show that TRAF2 is involved in CD40-mediated induction of APE/Ref-1 nuclear translocation and that the two proteins physically interact in vitro and in vivo. Moreover, treatment with the p38 inhibitor, SB203580 or site directed mutagenesis of the serine 54 (Ser(54)) in the MAP kinase consensus site present in APE/Ref-1 blocks its nuclear translocation caused by CD40-mediated B cell activation and reveals a potential role of p38 in this pathway. These data together uncovers a new signaling pathway regulating APE/Ref-1 nuclear translocation involving CD40-crosslinking, TRAF2 and p38.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, P.le Kolbe 4, I-33100 Udine, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Merluzzi
authors.forename: Orietta
authors.initials: O
authors.lastname: D'Orlando
authors.forename: Antonio
authors.initials: A
authors.lastname: Leonardi
authors.forename: Gaetano
authors.initials: G
authors.lastname: Vitale
authors.forename: Carlo
authors.initials: C
authors.lastname: Pucillo
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D005799:Genes, Dominant; D006367:HeLa Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D018448:Models, Immunological; D009154:Mutation / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D012694:Serine / Q000235:genetics; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D047428:Protein Kinase Inhibitors; D047992:TNF Receptor-Associated Factor 2; D023201:CD40 Ligand; D012694:Serine; D048051:p38 Mitogen-Activated Protein Kinases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase