Gadd45β mediates the protective effects of CD40 costimulation against Fas-induced apoptosis

Francesca Zazzeroni, Salvatore Papa, Alicia Algeciras-Schimnich, Kellean Alvarez, Tiziana Melis, Concetta Bubici, Nathan Majewski, Nissim Hay, Enrico De Smaele, Marcus E. Peter, Guido Franzoso*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

In B lymphocytes, induction of apoptosis or programmed cell death (PCD) by Fas (CD95/APO-1) is suppressed by the triggering of CD40. This suppression controls various aspects of the humoral immune response, including antibody affinity maturation. The opposing effects of these receptors are also crucial to B-cell homeostasis, autoimmune disease, and cancer. Cytoprotection by CD40 involves activation of protective genes mediated by NF-κB transcription factors; however, its basis remains poorly understood. Here, we report that, in B cells, Gadd45β is induced by CD40 through a mechanism that requires NF-κB and that this induction suppresses Fas-mediated killing. Importantly, up-regulation of Gadd45β by CD40 precedes Fas-induced caspase activation, as well as up-regulation of other NF-κB-controlled inhibitors of apoptosis such as Bcl-XL and c-FLIPL. In the presence of Gadd45β, the Fas-induced apoptotic cascade is halted at mitochondria. However, in contrast to Bcl-XL, Gadd45β is unable to hamper the "intrinsic" pathway for apoptosis and in fact appears to block Fas cytotoxicity herein by suppressing a mitochondria-targeting mechanism activated by this receptor. These findings identify Gadd45β as a critical mediator of the prosurvival response to CD40 stimulation and provide important new insights into the apoptotic mechanism that is triggered by Fas in B cells.

Original languageEnglish (US)
Pages (from-to)3270-3279
Number of pages10
JournalBlood
Volume102
Issue number9
DOIs
StatePublished - Nov 1 2003

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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