et al., 2000). It remains to be determined whether CKs cooperate with PKC or other
kinases in the phosphorylation of BID. The Ser/Thr phosphatase that
dephosphorylates BID and renders it susceptible to caspase-8-mediated cleavage in
response to death receptor engagement has yet to be identified.
Sequestration of BID by Bcl-xL—competition with BAX or BAKBH-3 domain-only members of the Bcl-2 family, such as BID, absolutely require
multidomain members of the Bcl-2 family (BAX, BAK) to induce apoptosis.
Antiapoptotic members of the Bcl-2 family, such as Bcl-xL, heterodimerize with BAX
or BAK, as well as BID (Cheng et al., 2001). While mutants of Bcl-xL that cannot
bind either BAX or BAK (bearing F131V or D133A substitutions) remain capable
of protecting cells from death receptor-induced apoptosis, Bcl-xL mutants that fail to
bind BID (bearing G138E, R139L, and I140N substitutions) are unable to inhibit
apoptosis (Cheng et al., 2001). These observations support a model in which
antiapoptotic Bcl-2 family members, such as Bcl-xL, sequester tBID in stable
mitochondrial complexes, thereby curtailing its ability to promote the allosteric
activation of BAX or BAK. In this scenario, proapoptotic multidomain members
(BAX, BAK) compete with antiapoptotic members (Bcl-2, Bcl-xL) for binding to
tBID to regulate the mitochondrial disruption and efflux required for the terminal
events of apoptosis.
4.5
Inhibitor-of-apoptosis proteins (IAPs)—sequestration of Smac/
DIABLO and inhibition of caspasesCaspases are directly regulated by interactions with inhibitor-of-apoptosis (IAP)
proteins. At least five mammalian homologs of the baculovirus IAP have been
identified. Four of these (cIAP-1, cIAP-2, XIAP, and NAIP) consist of an N-terminal
domain containing multiple copies of a so-called baculovirus IAP repeat (BIR) motif
(Birnbaum et al., 1994), and a C-terminal zinc-containing protein-protein interaction
domain (RING finger) (Lovering et al., 1993). The fifth member (survivin) contains
only the BIR domain. XIAP (X chromosome-linked IAP; also known as hILP),
cIAP-1, and C-IAP2 (but not NAIP) directly bind and inhibit effector caspases, such
as caspase-3 and caspase-7 (Deveraux et al., 1997; Roy et al., 1997). In addition, they
also prevent activation of procaspase-9 and procaspase-6 by upstream signals
(Deveraux et al., 1998). XIAP inhibits caspase-3 and caspase-7 via its second BIR
domain and BH2-terminal linker (Takahashi et al., 1998), and prevents activation
of procaspase-9 through a region containing its third BIR domain (BIR3) (Deveraux
et al., 1999). The BIR2 region facilitates caspase-binding, and the NH2-terminal
linker directly blocks the catalytic cleft of caspase-3 and caspase-7 (Chai, J. et al.,
2001; Huang et al., 2001; Riedl et al., 2001). Consistent with its ability to inhibit
multiple effector caspases, overexpression of XIAP can inhibit TNF-α-induced
apoptosis (Stehlik et al., 1998). While these direct interactions with caspases may be
DEATH RECEPTORS IN APOPTOSIS 13