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is reliant on the interaction of Map with EBP50 (NHERF1), which interacts with
Ezrin to link Map to the actin cytoskeleton (
Orchard et al., 2012
). During infection
it is hypothesized that localized actin rearrangement at the bacterial attachment
site is recognized by the Map-EBP50-ezrin complex, which recruits Cdc42 to the
attachment site leading to further actin polymerization. EspM activation of RhoA
results in stress fiber formation in a ROCK-dependent manner (
Arbeloa et al.,
2008
), while EspT induces formation of membrane ruffles (through the Rac1
effector Wave2), lamellipodia, and bacterial internalization (
Bulgin et al., 2009
).
The
Shigella
Rho GEF IpgB1 associates with the plasma membrane and was
previously shown to recruit the ELMO-Dock180 complex to the membrane to
activate Rac1 (
Handa et al., 2007
), whether this occurs in addition to its Rho-
GEF activity remains to be confirmed. IpgB1, but not IpgB2, is necessary for
efficient invasion of HeLa cells (
Ohya et al., 2005
;
Hachani et al., 2008
). How-
ever in polarized cells only a double IpgB1/B2 mutant showed significantly
reduced invasion (
Hachani et al., 2008
) and therefore the interplay between
these effectors in triggering host cell invasion requires further investigation.
No T3SS GAPs or GDIs have been identified to date in EPEC/EHEC or
Shigella
, however other T3SS effectors can modulate Rho GTPases in differ-
ent ways. The EPEC effector Cif stabilizes RhoA (
Cui et al., 2010
) resulting
in stress fiber formation (
Oswald et al., 1994
). Cif deamidates the ubiquitin-
like protein NEDD8, which in turn deactivates neddylated Cullin-RING ubiq-
uitin ligases, a substrate of which is RhoA. RhoA is therefore not ubiquitinated
and degraded when Cif is present (
Cui et al., 2010
). The EPEC/EHEC effec-
tor EspH subverts actin dynamics affecting filopodia and pedestal formation
(
Tu et al., 2003
). EspH inactivates mammalian RhoGEFs which contain the
Dbl-homology and pleckstrin-homology (DH-PH) domains, but does not inac-
tivate the bacterial RhoGEFs (
Wong et al., 2012
). This poses an interesting
scenario where EspH may potentially reduce a subset of the endogenous mam-
malian RhoGEFs in order for the bacterial RhoGEFs to take over cell signaling
for the benefit of the bacteria.
T3SS effectors can also modulate Rho GTPase signaling pathways by bind-
ing directly to the Rho GTPase effector, bypassing the need for Rho GTPase
activation. EspG and TccP/EspF
U
are examples of such effectors (
Selyunin and
Alto, 2011
). Rho GTPase effectors such as N-WASP and p21 activated kinases
(PAKs) have autoinhibitory Rho GTPase binding domains (GBD) which nor-
mally inhibit the activity-bearing domain (AD). For WASP the AD is a VCA
domain (verprolin homology, central hydrophobic and acidic regions) which
recruits the Arp2/3 complex while the PAK AD is a kinase domain. TccP/EspF
U
binds to the N-WASP GBD releasing the autoinhibition of N-WASP allowing
it to recruit Arp2/3 and nucleate actin (
Cheng et al., 2008
), as described above.
EspG binds to PAK releasing the kinase domain from autoinhibition, although
to date this has only been demonstrated in vitro (Selyunin et al., 2011). The
method of release and activation of the autoinhibited AD by these bacterial
effectors is different to the mechanism by which endogenous Rho GTPases
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