title: Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia.
abstract: The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders.
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Kavanagh
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Rodhe
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M A
authors.initials: MA
authors.lastname: Burguillos
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla and Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Venero
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, R8:03, Karolinska Institutet, Stockholm, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Joseph
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D024101:Mitochondrial Proteins; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053148:Caspase 3