Genetics of Apoptosis

studies on how stress in the ER is coupled to apoptosis have demonstrated that the
ER, like mitochondria, can directly initiate pathways to caspase activation and
apoptosis.
In this review, we attempt to summarize and clarify what is known about the
involvement of the ER in different apoptotic systems. The review is divided into three
sections. The first section highlights recent data on the mechanism by which stress
in the ER caused by conditions that compromise protein folding is converted into
an apoptotic response. The second section discusses the involvement of ER calcium
signals in apoptosis, with specific attention paid to Ca2+ signals between the ER and
mitochondria. Finally, we overview some of the protein complexes located at the ER
that have been proposed to play a role in apoptosis.

2.

ER stress-induced apoptosis

2.1

The unfolded protein response

The lumen of the ER provides an optimal environment rich in chaperones for the
proper folding and modification of proteins of the secretory pathway. These
maturation steps are required for secretory proteins to reach their intended cellular
destination and perform their designated function. An inability to fold efficiently
secretory proteins places a cell in a hazardous situation; it would fail to produce
properly targeted/functioning proteins for normal cellular processes, and potentially
generate toxic, malfolded proteins harmful to the organism. Eukaryotic cells have,
therefore, evolved an elaborate system, called the unfolded protein response (UPR),
to monitor and regulate the folding environment within the ER. When unfolded
proteins accumulate in the lumen, the UPR sends out survival signals to halt protein
synthesis and specifically upregulate ER resident chaperones and other regulatory
components of the secretory pathway (Travers et al., 2000), giving the cell a chance
to correct the environment within the ER (Patil and Walter, 2001). However, if the
damage is too strong and homeostasis cannot be restored, the mammalian UPR can
ultimately initiate apoptosis.
The UPR was first unraveled in yeast, where genetic screens identified a linear
pathway involving three genes: Irel, Hacl, and Rgl1 (see Sidrauski et al., 1998;
Kaufman, 1999; Patil and Walter, 2001 for excellent reviews). Ire1p is a trifunctional
ER transmembrane protein with an N-terminal luminal sensing domain and a
cytosolic serine/threonine kinase domain, followed by a C-terminal endoribonuclease
domain. In response to an accumulation of unfolded proteins within the ER, Ire1p
oligomerizes, causing trans-autophosphorylation and activation of its kinase domain.
This stimulates the endoribonuclease domain of Ire1p, which excises a short
inhibitory intron from Hacl mRNA though a nonconventional splicing reaction
involving Rgl1p, a tRNA ligase. The modified Hacl mRNA is now efficiently

98 GENETICS OF APOPTOSIS