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sufficient to abrogate NleC proteolytic activity (
Petty et al., 2010
;
Yen et al.,
2010
;
Baruch et al., 2011
;
Muhlen et al., 2011
;
Pearson et al., 2011
). Further-
more, NleC cleaves p65 within its conserved DNA-binding domain, suggesting
that other NF-κB family members containing the same sequence could be sub-
strates of NleC (
Baruch et al., 2011
). The acetyltransferase p300 was recently
identified as an additional target of NleC (
Shames et al., 2011
). p300 functions
as a co-activator in the transcription of many genes by acetylating p65 (among
other transcription factors), thereby enhancing expression of genes downstream
of κB-containing enhancers (
Chen et al., 2001
) such as IL-8. Overexpression
of p300 can indeed antagonize repression of IL-8 secretion induced by EPEC
infection (
Shames et al., 2011
). While infection with EPEC
nleC
mutant does
not result in increased IL-8 production, presumably due to functional redun-
dancy with NleE and NleB, infection with an EPEC
nleEC
double mutant or
an EPEC
nleBEC
triple mutant results in significantly higher IL-8 production
by host cells compared with infection with EPEC
nleE
or EPEC
nleBE
alone
(
Baruch et al., 2011
;
Pearson et al., 2011
). Thus, NleC appears to complement
the activities of NleE and NleB by eliminating activated p65/p50 and/or its acet-
yltransferase p300 that would positively influence transcription and expression
of pro-inflammatory cytokines.
Together with NleC, the effector NleD was identified as zinc-dependent
metalloprotease as it also harbors the consensus sequence (
142
HELLH
146
)
(
Marches et al., 2005
). NleD specifically targets MAP kinases JNK and p38
but not ERK, thereby blocking nuclear translocation of the AP-1 transcription
factor, which regulates multiple cell processes including inflammation, differ-
entiation, proliferation, and apoptosis (
Baruch et al., 2011
). Infection with an
EPEC
nleBECD
mutant results in an increase of expression and secretion of
IL-8 compared to the
nleBEC
mutant, indicating an anti-inflammatory role for
NleD (
Baruch et al., 2011
).
The NleH family of proteins is also conserved amongst EPEC and EHEC
strains and the C-termini of NleH1 and NleH2 proteins display significant amino
acid sequence similarity with the
S. flexneri
T3SS anti-inflammatory effector
OspG (
Kim et al., 2005
). NleH1 and NleH2 have critical roles in inhibiting host
cell apoptosis; however, these effectors have also been implicated in the sup-
pression of NF-κB activation. NleH1 and NleH2 decrease IκKβ-induced NF-κB
activity by decreasing TNFα-induced degradation by preventing ubiquitination
of phospho-IκBα. Although the mechanism is not clear yet, stabilization of IκBα
is dependent on conserved lysine residues K159 in NleH1 and K169 in NleH2
from EPEC E2348/69 respectively (
Royan et al., 2010
). It was recently shown
that the N-terminus of both NleH1 and NleH2 could bind the ribosomal protein
S3 (RPS3) (
Gao et al., 2009
). RPS3 is a non-Rel subunit of NF-κB complexes
(
Wan et al., 2007
). RPS3 is considered a 'specifier' subunit of NF-κB, because it
facilitates high-affinity binding of DNA and determines the specificity of NF-κB
for selected target genes (
Wan et al., 2007
). NleH1 of EHEC selectively blocks
the transcription of NF-κB target genes by attenuating nuclear translocation of
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