In summary, sustained ER stress can lead to an apoptotic reaction by unleashing
a multitude of diverse signals (Figure 1). By activating protein kinases such as JNK
and c-Abl, the ER may prepare the mitochondria to initiate cell death through the
release of apoptotic IMS proteins. JNK and c-Abl may directly phosphorylate
antiapoptotic targets at the surface of the mitochondria that normally inhibit BH3-
only molecules, or, conversely, directly or indirectly activate proteins that encourage
Cyt.c release. The increased cytosolic Ca2+ levels that follow ER stress result in
dephosphorylation and translocation of BAD to the mitochondria. However, BAD-
dependent activation of BAK and BAX, and Cyt.c release may not proceed until Bcl-2
is downregulated by CHOP. Meanwhile, following its activation at the ER
membrane, mature caspase-12 is released into the cytosol, where it may directly cleave
and activate downstream caspases in cooperation with the Cyt.c/Apaf-1/ caspase-9
complex.
Alternatively, caspase-12 may cleave other regulatory molecules that work in
conjunction with mitochondrial signals or that are relevant to the progression of
apoptosis in some other way. Future identification of caspase-12 substrates should
clarify this issue. It will also be important to understand how the ER coordinates
prosurvival signals with prodeath signals, and how it is decided that the efforts to
repair the secretory pathway are futile and that the death program should be triggered.
One possibility is that UPR simultaneously primes the cell to undergo apoptosis via
upregulation of CHOP, and activation of c-Abl, JNK, and BAD, while it upregulates
chaperones to relieve the stress. If the stress is not adequately dealt with within a
certain period of time, the ER might trigger a second signal that activates caspase-12,
bringing on full-scale activation of downstream caspases and execution of apoptosis.
THE ROLE OF THE ENDOPLASMIC RETICULUM IN APOPTOSIS 105