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1985
;
Oaks et al., 1986
).
ipaBCD
are absolutely required for invasion of mam-
malian cells and carry out post-invasion roles as secreted effectors (
Menard
et al., 1993
). An
ipaA
mutant is still invasive but has a 10-fold reduced ability
compared to wild-type (
Tran et al., 1997
). This operon also encodes a molecular
chaperone, IpgC (invasion plasmid gene), which binds IpaB and IpaC in the
bacterial cytosol prior to secretion and prevents their interaction and proteolytic
degradation (
Menard et al., 1994b
). Following secretion, IpaB and IpaC form
a complex that binds to molecules such as α5-β1 integrins and CD44 that are
present on the basolateral surface of host cells (
Watarai et al., 1996
;
Skoudy
et al., 2000
). After binding, the Ipa complex inserts into the host cell membrane
and causes a massive recruitment of host cell actin and other cytoskeletal factors
beneath the site of attachment. This exploitation of the host cell cytoskeleton
is observed with IpaBC-coated beads or whole
Shigella
bacteria and leads to
the formation of localized membrane projections that encompass and internal-
ize either beads or bacteria in roughly 5 minutes (
Menard et al., 1996
). Puri-
fied IpaC induces cytoskeletal reorganization, including formation of filopodia
and lamellipodial extensions on permeabilized cells (
Tran et al., 1999
). Inside
the host cell, IpaA interacts with vinculin to promote F-actin depolymerizaton.
Through this action, IpaA may promote formation of a pseudo-focal adhesion
complex that organizes the actin assembly complex beneath the bacterium and
directs optimal uptake of the pathogen (
Tran et al., 1997
;
Bourdet-Sicard et al.,
1999
).
IpaB serves several other roles in
Shigella
virulence that may be accom-
plished by separate domains of the protein. IpaB is required for escape of
Shigella
from both the phagosomal (following uptake by macrophages) and
endosomal (following uptake by epithelial cells) compartments (
High et al.,
1992
). This activity requires formation of a hydrophobic N-terminal alpha-helix
and is linked to the ability of IpaB to insert into host cell membranes and lyse
erythrocytes. In addition, IpaB binds to pro-caspase 1 in vitro and in vivo and
triggers hydrolysis of the cysteine protease (
Zychlinsky et al., 1994
). In macro-
phages, this activity leads to secretion of IL-1β (which initiates inflammation)
and induction of pyroptosis of the phagocyte.
The needle tip protein, IpaD, forms a pentameric ring at the end of the T3SS
needle and prevents secretion of the effector proteins (
Espina et al., 2006
). IpaD
also acts as an environmental sensor that triggers recruitment of IpaB to the
needle tip upon exposure to bile salts (
Olive et al., 2007
). Upon contact with
the cholesterol-rich plasma membrane of the mammalian cell, IpaC is recruited
to the needle tip where it associates with IpaB to form a translocon pore within
the host cell membrane (
Epler et al., 2009
). The IpaB/IpaC translocon is the
conduit through which effectors pass directly from the bacterium into the host
cell cytoplasm.
IpgB1 plays a critical role in invasion. It acts as a mimic of the host
small GTPase RhoG at the host plasma membrane, activates Rac1, and
stimulates membrane ruffling through the ELMO-Dock180 pathway (
Ohya
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