Type 3 secretion effectors - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 468

exchanger regulatory factor 2 NHERF2, which is localized at the plasma mem-
brane. Over-expression of NHERF2 leads to a decrease of the anti-apoptotic
activity of NleH potentially by retaining NleH at the membrane of the infected
cells ( Martinez et al., 2010 ). EspH can also induce apoptosis which is partially
inhibited by the bacterial Rho GEFs EspM2 and EspT (but not Map) ( Wong
et al., 2012 ). This inhibition may be achieved by modulation of MAPK and
NF-κB pathways ( Raymond et al., 2011 ) (which can regulate apoptosis), as
activation of Rac1 and RhoA has been reported to be involved in these pathways
( Hall, 2005 ).
Shigella induces DNA damage shortly after invasion of the cells, which pro-
motes the DNA damage response via phosphorylation of ataxia telangiectasia
kinase (ATM) and histone H2Ax, both of which are observed during Shigella
infection. ATM activation leads to the phosphorylation of pro-apoptotic tran-
scription factor p53 and prevents its interaction and degradation by the ubiquitin
ligase Mdm2, stabilizing p53 and inducing cell death. To prevent p53-induced
apoptosis, Shigella uses two different effectors. At the beginning of the infec-
tion, IpgD induces the phosphorylation of Mdm2, increasing its activity and
inducing the degradation of p53 ( Bergounioux et al., 2012 ). Shigella also pro-
motes the activation of calpain, a protease that degrades p53, preventing the
activation of the pro-apoptotic p53/NFκB signaling pathway, instead result-
ing in necrotic cell death. This activation is under the control of VirA, which
induces the proteolysis of the calpain inhibitor, calpastatin ( Bergounioux et al.,
2012 ). The EPEC/EHEC homologs of VirA, EspG, and EspG2, also induce acti-
vation of calpain and promote necrotic cell death and cell detachment. EPEC
and EHEC overcome this problem via another effector, Tir, which controls the
activation of calpain during the infection ( Dean et al., 2010 ).
Maintaining cell adhesion
Adhesion of the cell to the extracellular matrix (ECM) plays an important role
in many biological processes. At the cell-matrix contact point are dynamic and
tightly regulated structures known as focal adhesions (FA), an important com-
ponent of which are integrins (e.g. β1-integrin). Upon binding to the ECM and
activation, integrins induce the phosphorylation of focal adhesion kinase (FAK)
on tyrosine 397. Phosphorylation of FAK will then promote the recruitment of
the Src kinases which in turn phosphorylate tyrosines 576 and 577 of FAK. This
active form of FAK will then promote the formation of the FA. Moreover, FAK
also induces the phosphorylation of paxilin. This phosphorylation will then
induce an increased turnover of the FA leading to their disassembly.
One of many protein complexes that regulate FA turnover is the IPP com-
plex formed by integrin-linked kinase (ILK), and the adaptor proteins PINCH
and parvin. After activation of β1-integrin, this complex promotes clustering
of FAK with integrin and FAK phosphorylation ( Legate et al., 2006 ). Other
regulators of FA include the membrane protein CD98 which has been shown to