Gadd45 beta mediates the protective effects of CD40 costimulation against Fas-induced apoptosis.
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-kappa B transcription factors; however, its basis remains poorly understood. Here, we report that, in B cells, Gadd45 beta is induced by CD40 through a mechanism that requires NF-kappa B and that this induction suppresses Fas-mediated killing. Importantly, up-regulation of Gadd45 beta by CD40 precedes Fas-induced caspase activation, as well as up-regulation of other NF-kappa B-controlled inhibitors of apoptosis such as Bcl-xL and c-FLIPL. In the presence of Gadd45 beta, the Fas-induced apoptotic cascade is halted at mitochondria. However, in contrast to Bcl-xL, Gadd45 beta 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 beta 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.
Zazzeroni
Francesca
F
Gwen Knapp Center for Lupus and Immunoolgy Research, Ben May Institute, and Committee on Immunology, University of Chicago, IL 60637, USA.
Papa
Salvatore
S
Algeciras-Schimnich
Alicia
A
Alvarez
Kellean
K
Melis
Tiziana
T
Bubici
Concetta
C
Majewski
Nathan
N
Hay
Nissim
N
De Smaele
Enrico
E
Peter
Marcus E
ME
Franzoso
Guido
G
D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000502:physiology*; D017209:Apoptosis; D001402:B-Lymphocytes; D019013:CD40 Antigens / Q000502:physiology*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology*; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D019013:CD40 Antigens; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D019014:fas Receptor; C086470:GADD45B protein, human; D000097642:GADD45 Proteins