events, such as lipid transfer or release of reactive oxygen species. It has also been
reported that Bcl-2 can increase the capacity of mitochondria to store Ca2+ (Murphy
et al., 1996; Ichimiya et al., 1998; Zhu et al., 1999), presumably by preventing the
opening of the PTP, which releases matrix Ca2+. Thus, by localizing to both ER and
mitochondria, Bcl-2 might prevent apoptotic cross-talk between the two
compartments by lowering the amount of free [Ca2+]ER for IP 3 R/RyR release and by
increasing the tolerance of mitochondria to high Ca2+ loads. It cannot be excluded,
however, that Bcl-2 also functions by sequestering proapoptotic members (Cheng et
al., 2001), in which case the membrane location of Bcl-2 is irrelevant.
Proapoptotic, multidomain Bcl-2 family members may also exert their effects at
the ER in some cases. When overexpressed in human PC-3 cells, BAX and BAK
localize to both the mitochondria and ER, and induce caspase-independent emptying
of ER Ca2+ pools concomitant with an increase in [Ca2+]m (Nutt et al., 2002; Pan et
al., 2001). Coexpression of Bcl-2/Bcl-xL inhibits this Ca2+ mobilization, and an
inhibitor of mitochondrial Ca2+ uptake blocked BAX/BAK-induced increase in [Ca^2
+]m, Cyt.c release, and apoptosis (Nutt et al., 2002; Pan et al., 2001). Consistent with
a role for these proteins at the ER, BAK and BAX interact with the cytosolic tail of
the ER chaperone calnexin in yeast, and BAK-induced lethality in S. pombe is
dependent upon this interaction (Torgler et al., 1997). Moreover, Bcl-2cb5 can
inhibit BAX-induced apoptosis (Wang et al., 2001). BAX and BAK may have dual
roles at the ER and mitochondria and help facilitate cross-talk between the two
organelles. This could be achieved by stimulating IP 3 R/RyR-release channels, or
through formation of BAX/BAK pores in the ER membrane that facilitate Ca2+
transfer to the mitochondria. However, the ability of endogenous BAX and BAK to
modify Ca2+ signals during physiologic apoptotic pathways needs to be confirmed;
at present, it cannot be ruled out that the observed effects of BAX/BAK on ER Ca2+
homeostasis are either nonspecific or secondary to their effects on mitochondria.
4.
Other ER regulators of apoptosis4.1
BAP31
BAP31 is a ubiquitously expressed polytopic integral membrane protein of the ER
that has been implicated as both a chaperone for protein export and a regulator of
apoptosis. BAP31 was originally identified as an IgD interacting protein in B cells
(Kim et al., 1994), and was later proposed to influence cellubrevin and MHC I export
from the ER (Annaert et al., 1997; Spiliotis et al., 2000), and control ER retention
and degradation of the cystic fibrosis transmembrane conductance regulator (Lambert
et al., 2001). Our laboratory identified BAP31 as a Bcl-2 and Bcl-xL interacting
protein, a finding that suggested it could also function in apoptosis (Ng et al., 1997).
Further studies revealed that the C-terminal cytosolic tail of BAP31, which encodes
114 GENETICS OF APOPTOSIS