197: The apoptotic caspase cascade suppresses mitochondrial DNA-induced STING-mediated type I IFN production by dying cells

Activated caspases are a hallmark of apoptosis induced by the intrinsic (mitochondrial) pathway, but they are ultimately dispensable for this form of programmed cell death, and for the apoptotic clearance of cells in vivo. Combined with emerging evidence that caspases can inactivate damage-associated molecular pattern molecules (DAMPs), this has led to the suggestion that caspases are primarily activated not to kill, but to prevent dying cells from triggering a host immune response. Here we show that activation of Bak and Bax, the essential mediators of the intrinsic apoptosis pathway, induces mitochondrial (mt) membrane permeabilisation that results in the efflux of mtDNA into the cytosol. Cytosolic mtDNA activates cGAS, which initiates STING-mediated type I interferon (IFN) production. Activation of the caspase cascade prevents IFN production. Disabling the caspase cascade by pharmacological inhibition or genetic deletion of Caspase-9, Apaf-1, or Caspase-3/7 triggers secretion of IFN-β by apoptotic cells. In vivo , this precipitates an elevation in IFN-β levels and consequent hematopoietic stem cell dysfunction, which is corrected in Bak/Bax/Caspase-9 deficient mice. Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent.