13
Cell News 1/2015
Subversion of actin dynamic by bacterial pathogens
As discussed above, F-actin plays pivotal roles in the regulation
of cell shape, polarization and cellular trafficking. Many invasi-
ve bacterial pathogens have evolved to subvert these functions
for their own benefit (Figure 1). This is most often mediated
by secreted virulence proteins (invasion plasmid antigen (Ipa)
proteins) from these bacteria that are released by particular
secretion apparatuses (T3SS, type 3 secretion system) into the
host cell. Targets of bacterial subversion of actin dynamics are
among others tyrosine kinases, vinculin and predominantly small
GTPases of the Rho family (Figure 1A). Bacteria mainly modify
the activity of these enzymes by physical interaction and by
chemical modification to induce profound alterations in F-actin
that in the case of enteroinvasive bacteria such as
Shigella
flexneri
can induce the uptake of the pathogen by epithelial
cells (Valencia-Gallardo et al., 2015) (Figure 1B). A long list of
examples for both cases is known (for a recent review see (Baxt
et al., 2013)) including the SopE2 effector from
Salmonella
that
acts as a GEF (Rudolph et al., 1999; Friebel et al., 2001; Schlum-
berger and Hardt, 2005), YopE from
Yersina pseudotuber-
culosis
that acts as a GAP (reviewed in (Aepfelbacher et al., 2011))
and C3 exoenzyme of
Clostridium botulinum
that confers ADP-
ribosylation of Rho GTPases (reviewed in (Aktories, 2011)), just
to name some prominent cases.
The action of all these virulence factors ultimately results in
altered actin dynamics that supports the attachment, uptake,
cellular movement and cell to cell spread of the pathogens. A
promising strategy for the host to detect pathogen invasion thus
is to sense perturbations in GTPase controlled cellular processes
and changes in F-actin dynamics. Importantly, this pathogen
sensing is independent of MAMPs, which can be regulated by
pathogens to a certain extent for their own benefit. Such a con-
cept is rather new in the field of mammalian innate immunity
which still is mainly based on the view that foreign structures
on pathogens are sensed in a more or less direct manner by
host receptors. However, in plants it has been supposed that
the cytosolic receptors involved in plant immune responses can
function as sentinels of perturbations of cellular pathways, and
thus act as "guards" for cellular pathways (Dangl et al., 2013).
Interestingly, these plant cytosolic receptors share homology to
mammalian NLR proteins (Maekawa et al., 2011).
Molecular dissection of the function of mammalian NLR- and
related proteins in the context of bacterial infection now re-
cently brought up new exiting findings that suggest that similar
principles exist in mammalian cells.
It is known that perturbation of F-actin by depolymerizing drugs
affects pro-inflammatory signaling in myeloid cells (Kustermans
et al., 2008a; Kustermans et al., 2008b), however we could show
that actin depolymerization specifically affects NOD1 and NOD2
signaling (Legrand-Poels et al., 2007; Kufer et al., 2008; Bielig
et al., 2014). Moreover, evidence accumulates that Rho GTPase
activity also severely affects the outcome of PRR-mediated in-
flammatory responses. This was shown for TLR2- (Arbibe et al.,
2000), NOD1- and NOD2- (Legrand-Poels et al., 2007; Eitel et al.,
2008; Fukazawa et al., 2008; Keestra et al., 2013) and NLRP3-
mediated (Eitel et al., 2012) responses. The underlying molecular
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