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IcsB has a higher affinity for IcsA. This result indicates that IcsB caps IcsA to
protect
Shigella
from autophagy degradation. In addition, interaction between
IcsB and cholesterol is required for autophagy evasion but the ability of IcsB to
bind cholesterol and IcsA involves distinct domains (
Kayath et al., 2010
).
Other secreted effectors
Analysis of the culture supernatants from a
Shigella
mutant which displays con-
stitutive activation of the T3SS, revealed roughly 14 additional proteins that
are secreted (
Buchrieser et al., 2000
). Among these proteins are VirA, IpaH7.8
and IpaH9.8, and a family of proteins known as Osp (outer
Shigella
proteins).
VirA is a 44.7 kDa protein required for optimal
Shigella
invasion and intercel-
lular spread (
Uchiya et al., 1995
). It was first reported to possess microtubulin
cleaving activity (
Yoshida et al., 2006
) although this property of VirA has been
challenged (
Germane et al., 2008
). A recent report showed that VirA activates
cellular calpain which leads to degradation of p53 and inhibition of the p53/
NF-κB pathway. These effects prevent induction of apoptosis but ultimately
lead to necrotic cell death (
Bergounioux et al., 2012
). Members of the IpaH
family are encoded by alleles that are located on both the chromosome and
the virulence plasmid. They arose by gene duplication which was likely medi-
ated by adjacent insertion sequences (
Hartman et al., 1990
). The presence of
multiple copies of
ipaH
(which share a 3' constant region) on the plasmid and
chromosome of both
Shigella
and EIEC has led to its widespread use as a probe
to detect these organisms (
Venkatesan et al., 1989
).
ipaH7.8
is implicated in
virulence since mutants are impaired in phagosomal escape (
Fernandez-Prada
et al., 2000
). The E3 ubiquitin ligase activity of IpaH9.8 acts to diminish the
host inflammatory response by blocking the NF-κB pathway (
Rohde et al.,
2007
;
Asida et al., 2010
).
The
osp
genes, which encode secreted effector molecules, have a %G+C con-
tent very similar to that of genes in the entry region suggesting that they were
acquired at the same time as genes encoding the T3SS and Ipas (
Buchrieser
et al., 2000
). Several
osp
s have paralogs in the virulence plasmid that likely arose
through gene duplication. Many of the Osp proteins have been implicated in
modulation of the host inflammatory response via a variety of signaling path-
ways. These include OspB (
Zurawski et al., 2009
), OspC1 (
Zurawski et al., 2006
),
OspF (
Zurawski et al., 2009
;
Reiterer et al., 2011
), OspG (
Kim et al., 2005
), OspI
(
Sanada et al., 2012
) and OspZ (
Zurawski et al., 2008
;
Zhang et al., 2012
). More
details about the secreted effector proteins of
Shigella
can be found in Chapter 15.
One of the
Shigella
enterotoxins is encoded by
ospD3/senA
. This 60 kDa
T3SS effector protein induces fluid secretion in an animal model and alters the
electrical potential difference across a monolayer of cultured cell lines by an
unknown mechanism (
Nataro et al., 1995
). OspE is a secreted effector that binds
integrin-linked kinase and stabilizes adherence of infected cells, thus prolong-
ing and enhancing bacterial colonization of the epithelium (
Miura et al., 2006
;
Kim et al., 2009
).
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