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increase FA formation and FAK phosphorylation by interacting with β1-integrin
and affecting its function (
Cai et al., 2005
;
Yan et al., 2008
). FA turnover is also
controlled by the Rho GTPases RhoA and Rac1 via FAK (reviewed in
Tomar
and Schlaepfer, 2009
). Indeed, it has been shown that a number of Rho GEFs
or Rho GAPs can interact with FAK to specifically activate or inhibit these
Rho GTPases to promote or slowdown FA turnover and enhance cell migration
(
Tomar and Schlaepfer, 2009
).
The OspE effector family (OspE1/2 from
Shigella
and EspO1/2 from EHEC)
is able to modulate FA by interacting with ILK. Interaction between OspE and
ILK does not change ILK activity or stability or alter the formation of the IPP
complex, but it does lead to a decrease in phosphorylation of FAK (Y397) and
paxilin, an increase in the active form of β1-integrin and a decreased turnover
of β1-integrin. This mechanism serves to increase the membrane localization
of ILK and stabilizes and strengthens FA by inhibiting FA disassembly and
decreasing turnover. Infection of cells with an
ospE1
or
ospE2
mutant therefore
results in cell rounding (
Kim et al., 2009
) and cell detachment of polarized cells
(MDCK). Inhibition of the turnover of the FA and β1-integrin also leads to an
inhibition of the cell motility. In animals an
ospE
mutant displays decreased
colonization, inflammation, internal hemorrhaging, and diarrhea compared to
the wild-type strain suggesting that the inhibition of cell motility plays a critical
role during infection with
Shigella
.
Similarly, EPEC and EHEC have been shown to modulate FAK phosphory-
lation and FA turnover (
Shifrin et al., 2002
). One T3SS effector involved in
this process is EspZ, which has been reported to bind CD98 and induce phos-
phorylation of FAK (Tyr 576/577). Like OspE, EspZ inhibits cell detachment
in vitro (
Shames et al., 2010
) and plays a critical role during animal infection,
with an
espZ
mutant showing strong attenuation (
Deng et al., 2004
). The action
of EspZ is counteracted by another EPEC/EHEC effector, EspH which induces
cell rounding and detachment (
Dong et al., 2010
;
Wong et al., 2012
) by progres-
sively inducing disassembly of FA via a modulation of FAK concomitantly with
actin disruption (
Wong et al., 2012
). This function may be achieved through
Rho GTPase modulation, specifically through inhibition of Rac1 and partially
RhoA pathways, but not Cdc42 as cell rounding or detachment induced by
EspH can be counteracted by bacterial Rho GEFs SopE (a Rac1 RhoGEF from
Salmonella
), EspT or dominant positive of Rac1 and partially by EspM (
Wong
et al., 2012
).
DISRUPTING GUT INTEGRITY: DIARRHEAGENIC MECHANISM
The intestinal epithelium is a selectively permeable barrier which must allow
absorption of nutrients, electrolytes, and water while maintaining an effective
barrier to noxious substances and pathogens. Diarrhea is the result of an imbal-
ance in the absorption and secretion of ions and solute across the gut epithelium
and subsequent movement of water into the intestine to address the imbalance.
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