Type 3 secretion effectors - Escherichia coli: Pathotypes and Principles of Pathogenesis - page 464

the autophagosome. Shigella surface protein VirG/IcsA, which is required for
actin-based motility, is targeted by the autophagic component Atg5, but this det-
rimental interaction is inhibited by a second bacterial protein, the T3SS effector
IcsB ( Ogawa et al., 2005 ). icsB mutants are indeed targeted to and degraded
by the lysosome. Interestingly, septin cage-like structures are formed around
intracellular Shigella and are essential for the targeting of the bacterium to the
autophagy compartment ( Mostowy et al., 2010 ). Septins are GTP-binding pro-
teins that assemble in filaments and accumulate at the site of bacterial entry and
VirG-induced actin polymerization, thus impeding bacterial mobility. Stalling
of the bacteria in the cytosol allows autophagic recognition and subsequent bac-
terial clearance ( Mostowy et al., 2010 ). Strikingly, wild-type Shigella can evade
autophagy by delivering IcsB, which competitively binds to VirG to block Atg5
binding and enables the bacteria to evade autophagic recognition ( Ogawa et al.,
2005 ) ( Figure 15.2 C). Therefore, although Shigella induces autophagy upon
cell invasion, they have also developed mechanisms to evade autophagic recog-
nition ( Ashida et al., 2011 ).
CELL DEATH AND SURVIVAL
EPEC, EHEC, and Shigella are in contact with a large variety of cells dur-
ing infection and must prolong cell survival long enough to maintain and pro-
mote the infection or alternatively destroy the cells that are potentially harmful
for them. This cell death must be regulated to avoid any host response and to
achieve this, these bacteria have developed a large panel of effectors able to
modulate the cell cycle, induce or inhibit apoptosis, and promote cell adhesion.
Altering cell cycle
The cell cycle can be divided into four phases: mitosis (M) when cells are divid-
ing (further subdivided into prophase, metaphase, anaphase, and telophase);
post-mitotic phase (G1) when cells grow and have a high rate of protein synthe-
sis and metabolism; synthesis phase (S) characterized by DNA replication; and
pre-mitotic phase (G2), when cells are preparing to undergo mitosis. Interphase
comprises G1, S, and G2. Cell cycle progression is under the control of cyclin-
dependent kinases (CDKs) where a Cdk1-Cyclin B complex triggers mitosis
while Cdk2-Cyclin A/E or Cdk4-Cyclin D1 complexes trigger G1 to S phase
transition.
Cell cycle progression is further regulated by cyclin-dependent kinase
inhibitors (CKI). One family of CKIs is the CDK interacting protein/Kinase
inhibitory protein family (CIP/KIP) that is composed of three proteins p21 Cpi1/
WA F , p27 Kip1 , and p57 Kip2 . p21 binds and directly inhibits Cdk1-Cyclin B and
Cdk2-Cyclin E complexes, blocking cells in G2/M and G1/S phases respec-
tively (reviewed in Domingo-Sananes et al., 2011 ), while p27 binds Cdk2-
Cyclin A/E and Cdk4-Cyclin D1, blocking the cells in G1/S phase. CIP/Kip