Cross-talk between two apoptotic pathways activated by endoplasmic reticulum stress: differential contribution of caspase-12 and AIF.

Co-activation and cross-talk of different apoptotic pathways have been described in several systems however, the differential contributions of the different executors have not been well characterized. Here we report the co-translocation to the nucleus of caspase-12 and AIF in response to two endoplasmic reticulum (ER) stresses: protein misfolding and disruption of calcium homeostasis. As seen by treatment with pan-caspase inhibitor and calpain inhibitors, apoptosis is not mediated by executor caspases but by calpains. By reduction of AIF or caspase-12 expression we unraveled that AIF primarily controls apoptosis caused by changes in calcium homeostasis while caspase-12 has a main role in programmed cell death induced by protein misfolding. Nevertheless, the two apoptotic factors appear to reinforce each other during the apoptotic process, confirming that while the first response primarily involves one organelle, mitochondria and ER can influence each other in the apoptotic event.