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whereas uncontrolled cell death (necrosis) leads to massive inflammation and
a strong immune response. Apoptosis can be instigated by extracellular signals
(extrinsic pathway), such as cytokines (TNF-α or FAS), or by intracellular sig-
nals (intrinsic pathway), such as ER stress or organelle damage (mitochondria).
The execution of apoptosis is under the control of caspases, cysteine proteases
which cleave a large number of proteins and lead to the formation of apoptotic
blebs vesiculating from the dying cells that are phagocytosed by macrophages.
Inactive pro-caspases are auto-proteolysed or cleaved by other caspases to
become active. One of these, caspase-3 (an executional caspase) is commonly
used as a marker of apoptosis.
Some bacterial effectors have been shown to be able to induce apoptosis.
Five minutes post-translocation, EspF is found in the mitochondria (
Nougayrede
and Donnenberg, 2004
;
Nagai et al., 2005
), dependent on a mitochondrial tar-
geting signal localized in the N-terminal 70 aa (
Nougayrede and Donnenberg,
2004
). Translocation of EspF to the mitochondria induces a loss of mitochon-
drial membrane potential (∆Ψ
M
) and the release of cytochrome c, activation
of the caspases (including caspase-3) leading to cell death (
Nougayrede and
Donnenberg, 2004
;
Nagai et al., 2005
). EspF has been reported to bind and
degrade Abcf2, which can increase caspase-3 activation and cell death, however
the mechanism involved is unknown (
Nougayrede et al., 2007
).
At later stages of infection (after 48 h in IEC-6 intestinal epithelial cells)
EPEC expressing Cif induces caspase-3 activation and apoptosis (
Samba-
Louaka et al., 2009
). The catalytic domain of Cif is necessary for induction of
apoptosis and therefore apoptosis induction may be linked to cell cycle arrest
induced by Cif, although this has not been directly shown.
Shigella
induces a form of apoptosis termed pyroptosis in macrophages
(
Raqib et al., 2002
) which is dependent on the translocator IpaB (
Zychlinsky
et al., 1994
). Following
Shigella
cell invasion, IpaB localizes to the cytoplasm
(
Chen et al., 1996
) where it interacts with and then activates caspase-1 but not
caspase-2 or caspase-3 (
Hilbi et al., 1998
). Activation of caspase-1 induces the
release of IL-1β (
Chen et al., 1996
), an apoptotic inducer, leading to cell death
and bacterial release. This process appears to be restricted in epithelial cells.
Non-phagocytic cells infected with EPEC, EHEC, or
Shigella
show limited
signs of apoptosis early during infection despite delivery of these pro-apoptotic
effectors (
Mantis et al., 1996
), suggesting other mechanisms exist to inhibit
or slow down cell death. Indeed, cells or animals infected with an
nleH1
and
nleH2
double mutant present a high rate of apoptosis. By transfection, it has
been shown that both proteins can inhibit apoptosis induced by a global apop-
totic inducer or by ER stress (
Hemrajani et al., 2010
;
Robinson et al., 2010
).
NleH is a serine threonine kinase which localizes at the membrane of the cell
and at the ER. Interaction with the anti-apoptotic protein Bax inhibitor-1 at the
surface of the ER is essential to the anti-apoptotic activity of NleH, however its
kinase activity appears unnecessary (
Hemrajani et al., 2010
). NleH also has a
c-terminal PDZ binding domain which can interact with the sodium-hydrogen
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