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During infection this may permit localized dissociation between the membrane
and cytoskeleton to allow membrane ruffling and filopodia extension through
the manipulation of Rho GTPases by IpgB1 and IpgB2. The IpaA protein binds
to the focal adhesion protein vinculin ( Tran Van Nhieu et al., 1997 ), increasing
the association of vinculin with F-actin and inducing actin filament depolymer-
ization ( Bourdet-Sicard et al., 1999 ), which may be required for completion of
the entry process or for reappropriating actin.
In Shigella , actin-based motility occurs through the action of IcsA, an auto-
transporter rather than a T3SS effector, which recruits and activates N-WASP,
Arp2/3, polymerizing actin.
Rho GTPase modulation
Many T3SS effectors subvert host cell actin dynamics by disrupting Rho
GTPase signaling ( Bulgin et al., 2010 ). The Rho family GTPases are crucial in
the regulation of key cellular functions and the best characterized members are
Cdc42, Rac1, and RhoA, which trigger filopodia, lamelipodia/ruffles, and stress
fibers respectively ( Hall, 1998 ). Rho GTPases cycle between an active, GTP-
bound state (predominantly membrane associated) and an inactive GDP-bound
form (predominantly cytoplasmic). As shown in Figure 15.1 C, the exchange of
GDP for GTP is stimulated by guanine exchange factors (GEFs) to activate Rho
GTPases. Some RhoGEFs can also mediate interaction with effector molecules
to determine downstream signaling pathways. GTP hydrolysis is enhanced by
binding of GTPase-activating proteins (GAPs) resulting in inactive GDP-bound
Rho GTPase, again some GAPs can scaffold protein complexes. In addition,
GDP release is blocked by guanine nucleotide-dissociation inhibitors (GDIs)
maintaining the inactive state of Rho GTPases in the cytosol. Therefore these
regulators of Rho GTPases not only define the Rho GTPase activity of a mol-
ecule but also influence the formation of multiprotein complexes and hence
downstream signaling events.
A number of bacterial effector proteins have been described which modu-
late Rho GTPases and many were grouped on the basis of a WxxxE motif and
suggested to act as Rho GTPase mimics ( Alto et al., 2006 ). Structural infor-
mation helped establish that representatives of this family of effectors actually
act as RhoGEFs by binding to their respective Rho GTPases and inducing a
conformational change to allow GTP binding and hence activation ( Buchwald
et al., 2002 ; Ohlson et al., 2008 ). These include the EPEC/EHEC effectors
Map (Cdc42 GEF[53]), EspM (RhoAGEF[54]), and EspT[55] (likely Rac1 and
Cdc42 GEF, although direct binding has not been demonstrated) ( Bulgin et al.,
2009 ) and the Shigella effectors IpgB1 (a Rac1 and Cdc42 GEF) and IpgB2
(a RhoA GEF) ( Huang et al., 2009 ; Klink et al., 2010 ).
Activation of Cdc42 by Map results in localized transient filopodia formation
( Kenny et al., 2002 ; Berger et al., 2009 ). Map can polarize Cdc42 at the cell mem-
brane to form actin-rich protrusions in the absence of external stimuli. This reaction
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