Regulation of caspase-3 Processing by cIAP2 Controls the Switch Between Pro-Inflammatory Activation and Cell Death in Microglia

Cell Death Dis. 2014 Dec 11;5(12):e1565. doi: 10.1038/cddis.2014.514.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Caspase 3 / genetics
  • Caspase 3 / metabolism*
  • Cell Line
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Mice
  • Microglia / cytology
  • Microglia / enzymology*
  • Microglia / immunology
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Neurodegenerative Diseases / enzymology
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism
  • Protein Processing, Post-Translational
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Diablo protein, mouse
  • Inhibitor of Apoptosis Proteins
  • Mitochondrial Proteins
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Birc3 protein, mouse
  • Ubiquitin-Protein Ligases
  • Caspase 3