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Cell News 1/2015
Sensing of pathogen-induced F-actin perturbations –
a new paradigm in innate immunity?
Angelika Hausser, Kornelia Ellwanger & Thomas Kufer
Perspective
Summary
The F-actin cytoskeleton plays pivotal roles in cell shape, cell
migration and signaling. Many bacterial pathogens subvert the
actin regulatory machinery to assure pathogenicity. Recent
evidence now suggests that mammalian host cells are able to
sense pathogen induced perturbations in their F-actin network.
Here we provide a brief summary of our current understanding
of this emerging concept focusing on key molecules that are
supposed to be involved in sensing of pathogen-induced host
F-actin remodeling.
Introduction
Mammals evolved to respond to pathogen by means of immune
reactions. An immediate response towards invading pathogens
is provided by the innate immune system. Virtually any cell in
the body expresses particular receptors that are able to detect
conserved microbial structures. Triggering of these receptors
leads to the release of chemokines and cytokines to attract cells
of the adaptive immune system and to instruct adaptive immu-
ne responses, but also to the release of antimicrobial peptides
that can counteract microbial action at the site of invasion (Aki-
ra et al., 2006).
Within the recent decades many of these, so called pattern-
recognition-receptors (PRRs) have been identified and we know
in most cases the respective microbial ligand, termed microbe-
associated molecular pattern (MAMP) of these receptors. PRRs
exist as transmembrane proteins residing in the cell membrane
and in the endocytic compartments, but also in the cytoplasm.
Prominent examples of membrane bound PRRs are the Toll-like
receptors (TLRs), including the lipopolysaccharide receptor TLR4,
that is critically involved in septicemia (Kawai and Akira, 2011).
Cytosolic PRRs were recognized more recently and include the
family of Nod-like receptors (NLRs). In particular the NLR pro-
teins NOD1 and NOD2 are well established PRRs for cytosolic
bacterial peptidoglycan (PGN). Activation of NOD1 and NOD2
leads to stimulation of the NF-
κ
B and MAPK pathways, resul-
ting in transcriptional reprogramming and expression of pro-
inflammatory proteins (Kufer, 2008).
Recent work now suggests that PRR signaling is intimately
linked to F-actin and that changes in the activity of actin regu-
latory proteins e.g. the Arp2/3 complex and the actin depolyme-
rization factor cofilin, profoundly affects PRR mediated immune
responses. Moreover, it emerges that PRR signaling might be
used by the mammalian cell to sense perturbations of F-actin
by pathogenic bacteria that hijack the actin machinery to assure
their pathogenicity.
Here we will briefly summarize these novel functions of the ac-
tin cytoskeleton in innate immunity.
Regulation of host actin dynamics by the cofilin
signaling network
In eukaryotic cells the actin cytoskeleton responds to external
cues by a dramatic rearrangement that, for example, is observed
in migrating cells. Actin filaments are composed of monomeric
actin molecules that associate via non-covalent interactions.
Actin polymerization is a steady state process mainly driven
from the so-called barbed end of F-actin, by association of ATP-
loaded actin monomers. At the opposite end – the pointed end
– ADP-loaded actin monomers are released, and after exchange
of ADP for ATP these free actin monomers refill the monomeric
actin pool available to the actin polymerization cycle (review-
ed in (Pollard, 1990)). Actin polymerization requires nucleation,
which includes the formation of actin dimers and trimers and is
an energetically unfavorable process until actin tetramers are
formed. Actin nucleation is promoted by the so called nuclea-
tors, which reduce the energy barrier for the formation of actin
dimers or trimers (Sept and McCammon, 2001). In general, F-
actin is either organized as linear cables or branched networks.
Branched F-actin is generated at membrane protrusions such as
lamellipodia and invadopodia through the action of the actin
nucleator Arp2/3 complex, which binds to the sides of pre-exis-
ting filaments enabling the growth of new filaments at these si-
tes (reviewed in (Rotty et al., 2013) and (Mullins, 2000)). Actin-
binding proteins belonging to the ADF/cofilin family regulate
the disassembly of F-actin. These proteins are essential in all eu-
karyotes and can be found in three different isoforms in mam-
mals: ADF, cofilin-1 and cofilin-2 (reviewed in (Bamburg, 1999;
Bernstein and Bamburg, 2010)). Cofilin-1 is the main isoform in
nonmuscle tissue whereas cofilin-2 is predominantly expressed
in muscle cells. Here we will focus on cofilin-1 and refer thus to
it as cofilin. Cofilin severs F-actin filaments and thus increases
the number of free barbed ends, which serve as starting points
for further actin polymerization. In addition, the interaction
between cofilin and F-actin increases the rate of actin dissocia-
