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Prepublished online as a Blood First Edition Paper on July 10, 2003July 17, 2003; DOI 10.1182/blood-2003-03-0689.
Submitted March 4, 2003
Accepted June 19, 2003
Gadd45 mediates the protective effects of CD40 co-stimulation 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, and Guido Franzoso*
Ben May Institute, University of Chicago, Chicago, IL, USA
Department of Molecular Genetics, University of Illinois, Chicago, IL, USA
* Corresponding author; email: gfranzos{at}midway.uchicago.edu.
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- B transcription factors; however, its basis remains poorly understood. Here we report that, in B cells, Gadd45 is induced by CD40 through a mechanism that requires NF-B, and that this induction suppresses Fas-mediated killing. Importantly, upregulation of Gadd45 by CD40 precedes Fas-induced caspase activation, as well as upregulation of other NF-B-controlled inhibitors of apoptosis such as Bcl-xL and c-FLIPL. In the presence of Gadd45, the Fas-induced apoptotic cascade is halted at mitochondria. However, in contrast to Bcl-xL, Gadd45 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 Gadd45 as a critical mediator of the pro-survival response to CD40 stimulation and provide important new insights into the apoptotic mechanism that is triggered by Fas in B cells.
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