title: Neuronal caspase 2 activity and function requires RAIDD, but not PIDD.
abstract: Caspase 2 was initially identified as a neuronally expressed developmentally down-regulated gene (HUGO gene nomenclature CASP2) and has been shown to be required for neuronal death induced by several stimuli, including NGF (nerve growth factor) deprivation and Aβ (β-amyloid). In non-neuronal cells the PIDDosome, composed of caspase 2 and two death adaptor proteins, PIDD (p53-inducible protein with a death domain) and RAIDD {RIP (receptor-interacting protein)-associated ICH-1 [ICE (interleukin-1β-converting enzyme)/CED-3 (cell-death determining 3) homologue 1] protein with a death domain}, has been proposed as the caspase 2 activation complex, although the absolute requirement for the PIDDosome is not clear. To investigate the requirement for the PIDDosome in caspase-2-dependent neuronal death, we have examined the necessity for each component in induction of active caspase 2 and in execution of caspase-2-dependent neuronal death. We find that both NGF deprivation and Aβ treatment of neurons induce active caspase 2 and that induction of this activity depends on expression of RAIDD, but is independent of PIDD expression. We show that treatment of wild-type or PIDD-null neurons with Aβ or NGF deprivation induces formation of a complex of caspase 2 and RAIDD. We also show that caspase-2-dependent execution of neurons requires RAIDD, not PIDD. Caspase 2 activity can be induced in neurons from PIDD-null mice, and NGF deprivation or Aβ use caspase 2 and RAIDD to execute death of these neurons.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Ribe
authors.forename: Ying Y
authors.initials: YY
authors.lastname: Jean
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Goldstein
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzl
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stefanis
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Carol M
authors.initials: CM
authors.lastname: Troy
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D053420:CRADD Signaling Adaptor Protein / Q000096:biosynthesis*; D053143:Caspase 2 / Q000378:metabolism*; D002478:Cells, Cultured; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000172:deficiency / Q000494:pharmacology; D009474:Neurons / Q000201:enzymology*; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D053420:CRADD Signaling Adaptor Protein; C484481:Cradd protein, mouse; D053418:Death Domain Receptor Signaling Adaptor Proteins; C414729:Pidd1 protein, mouse; D020932:Nerve Growth Factor; C090208:Casp2 protein, mouse; D053143:Caspase 2