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

Daniela Sanges,Valeria Marigo

doi:10.1007/s10495-006-9006-2

Abstract

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.

Highlights

Apoptosis can be activated through extrinsic or intrinsic pathways
We show that caspase-12 and Apoptosis-inducing factor (AIF) concomitantly re-localize to the nucleus as a consequence of endoplasmic reticulum (ER) stress caused by tunicamycin treatment or by disruption of calcium homeostasis by thapsigargin treatment
We demonstrated that AIF and caspase-12 translocate to the nucleus in response to several apoptotic conditions, yet their co-localization appears to be a specific response to ER stress

Summary

Introduction

Apoptosis can be activated through extrinsic or intrinsic pathways. Extrinsic pathways preferentially activate caspases that are cysteine proteases mediating apoptotic death in a variety of cellular systems. There are several examples of intrinsic pathways mediated by the mitochondria and, in response to apoptotic stimuli, several proteins are released from the intermembrane space of the organelle into the cytoplasm. Among them is cytochrome c that is involved in formation of the apoptosome, which leads to the activation of executor caspases 1. Accumulating evidences suggest that other organelles, including the endoplasmic reticulum (ER) are major points of integration of pro-apoptotic signaling. Each organelle possesses sensors that detect specific alterations, locally activates signal transduction pathways and emits signals that ensure inter-organellar cross-talk. The ER senses local stress through chaperones, Ca2+-binding proteins and Ca2+ release channels, which can transmit ER Ca2+ responses to mitochondria

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