Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia

• Published in: Cell death & disease Vol. 5; no. 12; p. e1565
• Main Authors: Kavanagh, E, Rodhe, J, Burguillos, M A, Venero, J L, Joseph, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.12.2014; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/106; 13/2; 13/31; 14/19; 38/39; 38/77; 631/378/2596/1953; 631/378/371; 631/80/82/23; 692/699/375/365; Animals; Antibodies; Apoptosis; Baculoviral IAP Repeat-Containing 3 Protein; Biochemistry; Biomedical and Life Sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspase 3 - genetics; Caspase 3 - metabolism; Cell Biology; Cell Culture; Cell Line; Humans; Immunology; Inhibitor of Apoptosis Proteins - genetics; Inhibitor of Apoptosis Proteins - metabolism; Life Sciences; Medicin och hälsovetenskap; Mice; Microglia - cytology; Microglia - enzymology; Microglia - immunology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Neurodegenerative Diseases - enzymology; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Original; original-article; Protein Processing, Post-Translational; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.514

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.