Genetics of Apoptosis

5.

The role of the endoplasmic reticulum in

apoptosis

David G.Breckenridge and Gordon C.Shore

1.

Introduction

When a metazoan cell encounters an external or internal stress that disrupts its
physiologic processes, it is forced either to correct the problem or undergo
programmed cell death to ensure the health of the organism as a whole. To achieve
this, the cell has evolved sentinels that coordinate communication between subcellular
compartments, thereby linking diverse stress signals to the core death machinery.
Proper communication between organelles is also essential for the cell to synchronize
different stages in the initiation and execution of apoptosis, allowing a rapid and
efficient demise. Mitochondria are central regulators of apoptosis that store key
regulators of caspase activation and nuclear DNA degradation within their
intermembrane space (IMS) (see Chapter 7). In most cell-death pathways, the
commitment to execute apoptosis occurs when prodeath signals converge on
mitochondria, resulting in permeabilization of the outer membrane (OMM) and
release of apoptotic IMS proteins such as cytochrome c (Cyt.c) (Green and Reed,
1998; Ferri and Kroemer, 2001). Bcl-2 family members reside in the OMM and
control this step, with proapoptotic members facilitating the release of Cyt.c and
antiapoptotic members blocking it. In the cytosol, Cyt.c complexes with procaspase-9
and APAF-1, forming the apoptosome complex, which triggers a cascade of caspase
activation and subsequent proteolysis of caspase substrate molecules (Green and Reed,
1998).
Emerging evidence suggests that the endoplasmic reticulum (ER) also regulates
apoptosis by communicating with mitochondria and by initiating cell-death signals
of its own. The contribution of the ER to apoptosis is highlighted by the fact that
Bcl-2 family members have been localized to ER membranes, in addition to
mitochondria, and demonstrated to influence ER homeostasis directly. Calcium
release from the ER has been implicated as a key signaling event in many apoptotic
models, and, depending on the mode of Ca2+ release, it may directly activate death
effectors or influence the mitochondria to undergo apoptotic transitions. A growing
number of ER proteins have been shown to regulate apoptosis, some by interacting
with Bcl-2 family members, and others being caspase substrates. Moreover, recent