Type 3 secretion effectors - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 462

RPS3 without affecting p65 localization ( Gao et al., 2009 ). Nuclear transloca-
tion of RPS3 is triggered by IκKβ kinase-dependent phosphorylation at S209,
which enhances RPS3 association with nuclear importin-α. NleH1 specifically
inhibits IκKβ-dependent phosphorylation of S209 thus blocking RPS3 function
( Wan et al., 2011 ). Interestingly, another crucial target of IκKβ phosphorylation
in the NF-κB pathway is IκBα but whether NleH can block IκKβ-dependent
phosphorylation of IκBα remains to be elucidated as well as the mechanism
employed by NleH to block such post-translational modification.
By translocating into the host cell cytoplasm effectors such as NleE, NleB,
NleC, NleD, and NleH, EPEC and EHEC employ a highly coordinated strat-
egy to subvert inflammatory signaling pathways. This coordinated attack allows
the bacteria to establish infection and avoid rapid clearance by the host innate
immune response.
Similar to EPEC and EHEC Shigella delivers a subset of effectors via its
T3SS to subvert cellular and immune functions to promote infection ( Figure
15.2 B). During invasion and multiplication within the cells of the intestinal epi-
thelium Shigella peptidoglycan stimulates the intracellular PRR receptor Nod-
like receptor 1 (NOD1), which interacts with the serine-threonine kinase RICK
(also called Ripk2 or RIP2) to induce NF-κB and MAPK p38, ERK, and JNK
signaling ( Kanneganti et al., 2007 ). Both MAPK and NF-κB pathways compo-
nents are targeted by Shigella T3SS - delivered effectors ( Ashida et al., 2011 ).
As mentioned above, among its repertoire of T3SS effectors Shigella trans-
locates OspZ and OspG, homologs of NleE and NleH respectively. Similar to
NleE, OspZ blocks the translocation of NF-κB to the nucleus but whether OspZ
from Shigella shares the same cysteine methylase activity of EPEC NleE is not
currently known ( Zurawski et al., 2008 ; Newton et al., 2010 ).
A yeast two-hybrid screen showed that OspG is able to bind several ubiqui-
tinated E2 Ub-conjugating enzymes, including UbcH5 ( Kim et al., 2005 ). The
interaction with UbcH5 seems to inhibit E2 activity, which is indispensable
for the proper activation of the E3 Ub ligase SCFβ TrCP , the specific SCF com-
plex that controls IκBα degradation. Therefore, OspG negatively regulates the
NF-κB inflammatory response by interfering with the proteasome-dependent
degradation of IκBα. OspG also displays kinase activity and induces its auto-
phosphorylation. This activity appears to be necessary for the function of
OspG, but does not seem to be involved in the phosphorylation of IκBα before
ubiquitination and proteasome-mediated degradation. Consistent with the OspG
inhibiting SCFβ TrCP activity, epithelial cells infected with S. flexneri wild-type
strain, but not an ospG mutant, accumulate phosphorylated IκBα and the ospG
mutant induced a much stronger inflammatory response during infection in vivo
than the wild-type strain ( Kim et al., 2005 ).
IpaH9.8 is another effector delivered by Shigella into host cells that inter-
feres with the innate immune response. Once injected into the host cell IpaH9.8
translocates to the nucleus ( Toyotome et al., 2001 ) and has been shown to be an
E3 Ub ligase ( Rohde et al., 2007 ). In vitro, IpaH9.8 displayed ubiquitin ligase