TRAF2 and p38 are involved in B cells CD40-mediated APE/Ref-1 nuclear translocation: a novel pathway in B cell activation.

Publisher: Pergamon Press Country of Publication: England NLM ID: 7905289 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0161-5890 (Print) Linking ISSN: 01615890 NLM ISO Abbreviation: Mol Immunol Subsets: MEDLINE

Original Publication: Oxford, Elmsford, N. Y., Pergamon Press.

B-Lymphocytes/*enzymology ; CD40 Antigens/*metabolism ; Cell Nucleus/*metabolism ; DNA-(Apurinic or Apyrimidinic Site) Lyase/*metabolism ; Lymphocyte Activation/*immunology ; TNF Receptor-Associated Factor 2/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism; B-Lymphocytes/drug effects ; B-Lymphocytes/immunology ; CD40 Ligand/metabolism ; Cell Membrane/drug effects ; Cell Nucleus/drug effects ; Genes, Dominant ; HeLa Cells ; Humans ; Lymphocyte Activation/drug effects ; Models, Immunological ; Mutation/genetics ; Protein Binding/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Transport/drug effects ; Serine/genetics ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors

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.

0 (CD40 Antigens)
0 (Protein Kinase Inhibitors)
0 (TNF Receptor-Associated Factor 2)
147205-72-9 (CD40 Ligand)
452VLY9402 (Serine)
EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
EC 4.2.99.18 (APEX1 protein, human)
EC 4.2.99.18 (DNA-(Apurinic or Apyrimidinic Site) Lyase)

Date Created: 20070630 Date Completed: 20071109 Latest Revision: 20171116

20240829

10.1016/j.molimm.2007.05.010

17599408