Type 3 secretion effectors - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 472

Cl - absorption by targeting the down-regulated in adenoma (DRA) Cl - /OH -
exchanger ( Gill et al., 2007 ). EspG and EspG2 are responsible for the inter-
nalization of DRA into a subapical vesicle pool, thus reducing the amount
of surface-localized and functional DRA ( Gill et al., 2007 ). While EspG
was originally described to degrade microtubules it has recently been shown
to act as a RabGAP trapping Rab GTPases in their inactive GDP bound
form and thus altering cellular signalling pathways (Dong et al 2012). Addi-
tionally EspG can also bind the Golgi matrix protein GM130, p21-activated
kinases (PAKs) and ADP-ribosylation factors (ARFs) ( Clements et al., 2011 ;
Selyunin et al., 2011) acting as a molecular scaffold to regulate host signal-
ing cascades. EspG can interact with ARFs and Rabs simultaneously and
by interacting with activated, membrane-embedded ARFs, EspG potentially
transforms ARF activation into Rab inactivation at appropriate endomem-
branes. EspG can also bind PAKs and ARFs simultaneously; the EspG-ARF
interaction prevents GTP hydrolysis by ARF-GAPs and EspG-PAK interac-
tion prevents PAK autoinhibition, thus locking both ARF and PAK in their
active states (Selyunin et al., 2011). EspG overexpression disrupts the struc-
ture of the Golgi apparatus and decreases protein secretion and receptor traf-
ficking ( Clements et al., 2011 ; Selyunin et al., 2011), which may contribute
to the aberrant DRA localization during infection.
Diarrhea can also be caused by attenuation of Na + absorption, which is
primarily mediated by Na + /H + exchangers (NHEs). EPEC differentially regu-
lates two apical NHEs, increasing NHE2 activity and decreasing NHE3 activ-
ity dependent on the T3SS ( Hecht et al., 2004 ). EspF appears responsible for
decreasing NHE3 activity in EPEC-infected cells, although the mechanism is
not yet known. The NHE regulatory factors NHERF1 and NHERF2 appear to
also contribute to EPEC-induced down-regulation of NHE3, but whether this
occurs through EspF is unclear ( Hodges et al., 2008 ). Interestingly, while NHE3
activity is typically coupled to the DRA exchanger through interaction with
NHERF proteins ( Lamprecht et al., 2002 ), EPEC appears to use two different
effector proteins, EspF and EspG, to individually target and disrupt the function
of these Na + /Cl - exchangers.
EPEC alters another route of Na + uptake: the Na + /glucose cotransporter
SGLT1 which is active only in the presence of glucose. Wild-type EPEC, but not
an EPEC map/tir/espF/intimin quadruple mutant, rapidly inactivates SGLT-1
within 30 minutes of infection by altering its location from the apical surface to
become mainly intracellular ( Dean et al., 2006 ). Map and EspF appear to play
major but redundant roles in this inactivation of SGLT, although the molecular
mechanism of relocalization is unknown.
Aquaporins (AQP) are water and water/glycerol channels that are respon-
sible for the rapid transport of water across membranes. In infected colonocytes
AQP2 and AQP3 appeared to relocalize from the membrane to the cytoplasm
and this relocalization was dependent on EspF and EspG ( Guttman et al., 2007 ).
The redistribution of aquaporins by EspF and EspG may be indirect as the host