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Bacterial mechanotransduction
Alexandre Persat
Bacteria rapidly adapt to changes in their environment by essay is to highlight the recent findings demonstrating
leveraging sensing systems that permanently probe their that bacteria can sense mechanical signals and transduce
surroundings. One common assumption is that such systems these into biochemical processes to adapt their behaviors
are responsive to signals that are chemical in nature. Yet, to the local mechanical environment.
bacteria frequently experience changes in mechanical forces,
for example as they transition from planktonic to sessile states. Deconstructing mechanotransduction into the simple
Do single bacteria actively sense and respond to mechanical switch-like model illustrated in Figure 1 provides a
forces? I here briefly review evidence indicating that bacteria general and accessible view of a sometimes-complex
actively respond to mechanical stimuli, and along concisely phenomenon. This model consists in the succession of
describe their intricate machinery enabling the transduction of three elementary events: mechanotransmission, mechan-
force into biochemical activity. osensing and mechanoresponse [3]. Mechanotransmitting
components are structures that bear and propagate the
Address
applied force. These are coupled with mechanosensors
School of Life Sciences, EPFL, Lausanne, Switzerland
that modulate their biochemical activity in response to
Corresponding author: Persat, Alexandre (alexandre.persat@epfl.ch) transmitted forces. Finally, mechanosensors induce a
downstream mechanoresponse by modulating specific
developmental programs.
Current Opinion in Microbiology 2017, 36:1–6
This review comes from a themed issue on Cell regulation
This model successfully describes multiple mechano-
Edited by Petra Dersch and Michael Laub transduction systems in eukaryotes [3]. For example
cytoskeletal components (e.g., actin or tubulin in cilia)
transmit forces to membrane-associated mechanosensi-
tive proteins (e.g., mechanosensitive channels or focal
http://dx.doi.org/10.1016/j.mib.2016.12.002 adhesion complexes). This leads to a wide variety of
1369-5274/# 2017 Elsevier Ltd. All rights reserved. mechanoresponses that include rapid influx of ions
through membranes, feedback into mechanosensitive
components, transcriptional regulation and morphogene-
sis [3,4].
The examples of bacterial mechanotransduction I high-
light below reveal the role of pili, flagella or the outer
‘‘Nous sommes de bien petites me´caniques e´gare´es par
membrane as mechanotransmitters for forces generated
les infinis’’
by surface contact or fluid flow. These are coupled with
Blaise Pascal
two-component chemosensory-like systems that act
(We are such small machinery misplaced by infinity)
as mechanosensing components. Finally, mechanore-
sponses are diverse as single bacterial cells modulate
Introduction motility, activate virulence or initiate biofilm formation
Forces are ubiquitous in the natural environments of upon force sensing.
microbes. Bacteria routinely experience forces generated
by fluid flow or by contact with the surface of other cells, Mechanotransduction through type IV pili
biological gel matrices or abiotic materials [1]. However, Pseudomonas aeruginosa forms biofilms, possesses a sur-
mechanics have rarely been considered as a signal that face-specific twitching motility machinery, and disarms
bacteria could sense and respond to. In contrast, experi- potential predatory cells by injecting toxins upon contact
mental demonstrations of force sensing in eukaryotes are with a host. P. aeruginosa thus seems equipped to thrive
numerous and mechanotransduction has emerged as a on surfaces. Single cells frequently transition between
central process in their cell biology [2]. Single mammalian free swimming and attached states so that regulating
cells sense forces generated by fluid flow, by contact with these surface-specific phenotypes based on contact con-
extracellular matrices or by other cells, to which they stitutes an optimum strategy for rapid and efficient
actively respond. Bacteria possess a cohort of sensing deployment. Consistent with this, we have demonstrated
systems whose input signals remain unidentified, some that P. aeruginosa rapidly activates specific transcriptional
of which could potentially participate in transducing programs upon surface contact by leveraging a mechan-
forces into a developmental response. The intent of this otransduction system (Figure 2) [5 ].
www.sciencedirect.com Current Opinion in Microbiology 2017, 36:1–6
2 Cell regulation
Figure 1 FORCE (INPUT )
MECHANOTRANSMISSION
MECHANOSENSING MECHANORESPONSE ( OUTPUT)
Current Opinion in Microbiology
A switch-like model for bacterial mechanotransduction. Contact with a surface and fluid flow generate forces that are mechanically transmitted by
force bearing structures (mechanotransmission). These are coupled with mechanosensors that modulate their biochemical activity upon force
transmission which eventually yield a mechanoresponse such as transcriptional regulation.
In P. aeruginosa, the second messenger cyclic adenosine timescales, we provided evidence that upregulation of the
monophosphate (cAMP) activates the transcription factor cAMP/Vfr-dependent pathways upon surface contact is a
Vfr, which positively regulates surface-specific develop- response to mechanical input [5 ]. We went on to iden-
mental programs including type III secretion systems and tify its corresponding mechanotransmitting and mechan-
twitching motility, while repressing swimming motility osensitive components.
[6]. Vfr-dependent gene expression is elevated in colonies
grown on solid surfaces compared to liquid grown cells Type IV pili (t4p) are long and thin organelles that
[7,8 ]. Using a fluorescent transcriptional reporter to alternately extend and retract from cell poles by succes-
characterize responses at the single cell level and at short sive polymerization and depolymerization. As cells en-
counter surfaces, their extended t4p tether to the surface
Figure 2
so that subsequent retraction pulls the cell forward, thus
powering surface-specific twitching motility [9]. The
t4p main building block of t4p fibers is the major pilin subunit
PilA. Polymerization and depolymerization of PilA mono-
mers is powered by the extension motor PilB and the
retraction motor PilT, respectively [9]. Altogether, t4p are
mechanically actuated organelles that bear mechanical
load (tension) upon attachment and retraction. +P
PilA
The surface-induced increase in cAMP levels is depen-
PilJ ChpA PilG
tension dent on the t4p major pilin subunit PilA, showing that t4p
enable P. aeruginosa to mechanically sense contact
[5 ,8 ]. Additionally, mutations in the extension and
retraction motors PilB and PilT, but also attachment
t4p virulence
to softer, less dense substrates, diminished the magni-
tude of mechanoresponse [5 ]. In summary, both t4p
Current Opinion in Microbiology
fibers and the tension they experience during retraction
are required for effective mechanical signaling, indicat-
Illustration of the Pil-Chp mechanotransduction system in P.
ing that t4p act as mechanotransmitters. In that sense, t4p
aeruginosa. Type IV pili (t4p) extend and retract from the cell pole.
are reminiscent of actin filaments experiencing tension
When t4p attach to a surface, tension generated in the t4p fiber
signals to the methyl accepting chemotaxis protein PilJ via PilA pilin generated by myosin when signaling to focal adhesion
subunits. This induces transfer of a phopshoryl group from the mechanosensors [10].
histidine kinase ChpA to the response regulator PilG. As a result, the
adenylyl cyclase CyaB increases rate of cAMP production, thereby
T4p themselves may be sensitive to forces: measure-
inducing Vfr-dependent transcription. This mechanoresponse includes
upregulation of virulence factors, notably components of the type II ments on purified pili demonstrate that fibers can change
and III secretion systems. conformation under tension. In particular, pulling onto
Current Opinion in Microbiology 2017, 36:1–6 www.sciencedirect.com
Bacterial mechanotransduction Persat 3
singles fibers with an atomic force microscope produces suggests that flagella are coupled with a mechanosensor
force displacement curves characteristic of two distinct detecting increased load. Consistent with this, a variety of
stable conformational states: a relaxed state and a species respond to surface contact in a flagellum-depen-
stretched state induced by tension [11]. Moreover, artifi- dent manner. These systems have been reviewed in
cially stretched Neisseria gonorrhea t4p have reduced width depth elsewhere [20]. I only here briefly highlight the
and reveal epitopes which are buried in non-stretched example of Bacillus subtilis where mechanoresponse
fibers [12]. Such mechanically induced stable conforma- depends on a two-component chemosensory system.
tional changes could thereby initiate a mechanosensing
cascade. Environmental B. subtilis forms robust, surface associated
biofilms [21]. Flagella mediate biofilm formation as
T4p function depends on the two-component chemosen- mutants in flagellar stator overproduce extracellular poly-
sory system Chp. Mutants in Chp components exhibit meric substances (EPS) [22]. Cairns et al. further dem-
reduced twitching motility, but retain their ability to onstrated that mechanical inhibition of flagellar rotation
produce t4p [13,14]. Chp thereby represents an attractive by antibody binding or by overexpressing the flagellar
candidate to read out t4p mechanical states. Consistent clutch protein EpsE also stimulated EPS production,
with this, we showed that the Chp sensory system med- indicating that biofilm formation constituted a mechan-
iates mechanoresponse by stimulating the activity of the oresponse [23]. Here mechanoresponse depends on the
adenylyl cyclase CyaB [5 ]. The Chp system is homolo- two-component system DegS/DegU: DegS is a histidine
gous to the Che chemotaxis system of Escherichia coli. A kinase that phosphorylates the response regulator DegU
methyl-accepting protein, PilJ, senses external stimuli to upon environmental signal sensing. Phosphorylated
control phosphorylation of its cognate histidine kinase DegU upregulates genes coding for biofilm matrix com-
ChpA, and its corresponding response regulator PilG ponents (Figure 3). Thus DegS senses a signal generated
(Figure 2) [13]. Bacterial two-hybrid experiments indi- by inhibition of flagellum rotation by a mechanism that
cate that PilA interacts directly with PilJ [5 ]. This is has so far not been clearly described.
consistent with a model where PilJ senses tension-in-
duced changes in t4p during retraction. A candidate mechanosensor is still needed to fully de-
scribe flagellar mechanotransduction with a switch-like
In summary, a mechanotransduction model in P. aerugi- model. A popular hypothesis consists in attributing
nosa consists in mechanotransmission via t4p coupled a disruption of proton motive force to inhibition of
with mechanosensation via the Chp system, which acti- flagellum rotation [20]. However, attachment to charged
vates the cAMP/Vfr-dependent transcriptional mechan-
oresponse. Other gamma-proteobacteria possess t4p-Chp
Figure 3
systems, indicating that it could commonly enable rapid
adaptation to life on surfaces [13,15]. For example, t4p
mechanosignaling may regulate processes as fundamental flagellum
as cell size homeostasis in surface-associated Shewanella
oneidensis populations [16]. I also note that P. aeruginosa
regulates other phenotypes upon surface contact which
deploy on longer timescales and where the contribution of
mechanics may play a central role [8 ,17,18]. One system
is dependent on the PilY1 protein, which localizes at the motors +P
outer membrane and is also a minor component of t4p [7].
PilY1 mediates adaptation to surface association down- torque
DegS DegU
stream of the t4p-Chp system [8 ]. stator
Flagellar mechanotransduction
As swimming bacteria transition from planktonic to ses-
biofilm
sile states, the surface impedes the motion of their
Current Opinion in Microbiology
flagella. Viscous or steric interactions with the wall may
inhibit or abolish their rotation. Thus, flagella could
Flagella coupled with the two-component system DegS/DegU enable
transmit forces experienced during surface contact.
mechanotransduction in Bacillus subtilis. Contact with a surface
increases the torque applied onto flagella thereby repressing rotation.
A clear indication of flagellum-dependent mechanosen- This generates a signal, possibly an increase in proton flux or
recruitment of additional motor units, which is readout by the DegS
sation comes from the ability of the E. coli flagellar motor
histidine kinase. Upon sensing, DegS transfers phosphoryl groups to
to adapt to an increase in torque. In E. coli, inhibition of
DegU, inducing transcriptional mechanoresponse. This response
flagellum rotation induces recruitment of additional includes upregulation of EPS matrix proteins involved in biofilm
motor units, thereby adapting rotation rate [19]. This formation.
www.sciencedirect.com Current Opinion in Microbiology 2017, 36:1–6
4 Cell regulation
Figure 4
surfaces modulates intracellular pH and ATP activity,
including non-flagellated species [24 ,25]. Consequently,
surface chemistry may also contribute to surface-induced envelope,
CpxR
responses that depend on proton flux. Furthermore, evi- +P virulence
dence demonstrating that flagella contribute to signal cell enveloppe IM
transduction by transmitting forces as opposed to promot- CpxA
ing surface adhesion is in some cases lacking. Therefore,
peptidoglycan
demonstrating flagellar-based mechanotransduction still
requires careful physical and biochemical characterization
NlpE OM
to determine the dependence of mechanoresponse on
applied force and to clearly identify mechanosignaling force networks.
Current Opinion in Microbiology
Mechanotransduction through the cell
envelope NlpE coupled with the two-component regulatory system CpxA/CpxR
is a potential mechanosensitive system. Contact with hydrophobic
When attached a solid substrate, a bacterium experi-
surfaces activates to the outer membrane protein NlpE, possibly
ences an adhesion force. This force generates mechani-
through membrane deformation inducing a conformational change.
cal stress yielding measurable deformations of the cell
Activated NlpE signals to the histidine kinase CpxA, inducing
envelope [26,27]. Intuitively, mechanosensitive chan- phosphorylation of the response regulator CpxR thereby activating
nels, which are sensitive to membrane tension, could be transcriptional mechanoresponse. The response includes upregulation
of periplasmic repair proteins in E. coli K-12, and further includes
sensitive to forces generated upon attachment [28].
virulence factors in pathogenic strains such as EHEC.
Whereas their eukaryotic counterparts are integral
mechanosensing components for example in neurosen-
sory mechanotransduction [4], in bacteria their sensitiv-
ity to forces has only been demonstrated by suction of it is localized at the outer membrane, which bears me-
spheroplast membranes or by changes in osmolarity chanical stress during adhesion (Figure 4).
[28,29]. There is to my knowledge no clear evidence
for activation of mechanosensitive channels upon appli- How adhesion force acts on NlpE and stimulates CpxA
cation of exogenous forces on intact cells, possibly as a signaling is unknown. One possibility is that surface
consequence of their localization to the inner membrane contact induces a conformational change in NlpE, which
where they are protected from the physical environment CpxA reads out as a misfolded protein. Mechanotransmis-
by the stiff cell wall. Still, could bacteria possess similar sion could occur through outer membrane tension or
protein components to sense deformation of their outer compression upon contact. Another model would involve
membrane? slender structures such as fimbriae acting as levers ampli-
fying deformations, in a manner that is analogous to cilia
One system may be responsive to mechanical stresses on deformations inducing ion channel gating [4].
the cell envelope. The CpxA/CpxR E. coli two-compo-
nent system senses and responds to a variety of signals The Cpx system is widespread among Gram negatives.
described as envelope perturbations, for example mis- Beyond maintaining periplasmic integrity, Cpx regulates
folding of periplasmic proteins [30]. In response, Cpx a variety of phenotypes including virulence [32,33]. Alas,
rescues the integrity of periplasmic proteins. CpxA is a in these examples, the dependence of virulence on sur-
histidine kinase associated with the inner-membrane. face contact is rarely tested. Only one recent study by
Upon sensing input at the periplasm, CpxA phosphory- Shimizu and co-workers demonstrates that the NlpE-Cpx
lates the cytoplasmic response regulator CpxR, which system regulates the type III secretion system in enter-
initiates transcriptional response [30]. ohemorrhagic E. coli (EHEC) upon contact with hydro-
phobic surfaces [34 ].
An overlapping signaling pathway repurposes the Cpx
system to sense surfaces (Figure 4). Attachment to hy- Mechanotransduction in enterohemorrhagic
drophobic surfaces activates CpxR-dependent transcrip- E. coli
tion [31]. CpxA mutants are insensitive to contact EHEC strain O157:H7 is a common intestinal pathogen
demonstrating that CpxA might sense a signal induced that causes hemorrhagic colitis. It leverages a variety of
by surface attachment. Furthermore, the outer membrane virulence factors including toxins, secretion systems and
protein NlpE is required for surface-dependent Cpx adhesins to colonize its host and cause inflammation.
activation while it is not required for sensing misfolded Some of these factors are encoded in the locus of enter-
proteins [31]. Thus, NlpE might constitute a surface- ocyte effacement (LEE) pathogenicity island. Signals
sensor whose state is readout by the Cpx two-component such as metabolites or carbon dioxide levels regulate
system. NlpE is an attractive candidate mechanosensor as LEE expression via the LEE encoded regulator Ler [35].
Current Opinion in Microbiology 2017, 36:1–6 www.sciencedirect.com
Bacterial mechanotransduction Persat 5
Recently, the Krachler group identified mechanical stim- Because mechanotransduction is inherently coupled
ulation as another signal stimulating LEE expression with chemistry through overlapping regulatory process-
[36 ]. Using a fluorescent reporter for the LEE1 tran- es, experimental demonstrations require careful design
scriptional unit, they demonstrated that single E. coli cells and control of physical and chemical environments.
induced LEE expression upon host cell contact. Reporter Moreover, bacteria possess chemistry-based surface
fluorescence increased for cells in contact with glass sensing systems, for example through sensing of
coated with poly-L-lysine, antibodies and adhesion self-secreted compounds [37,38,39]. As a result surface
receptors, but not with bare glass. This may reflect a sensing systems that respond to multiple substrate
dependence of mechanoresponse on force as all three chemistries are not necessarily mechanosensitive. Con-
coatings increase adhesion strength [37]. versely, a surface sensing system that is specific to a
given surface chemistry cannot be ruled out as mechan-
In the gut, EHEC is subject to the flow of intestinal fluid. osensitive, as mechanotransmitters might have affinities
Alsharif, Krachler and co-workers demonstrated that flow to specific chemical moieties of a surface. Shear-
further induced ler1 expression in bacteria attached to sensitive catch bonds formed by the adhesin FimH is
host cells [36 ]. This occurred in a flow regime generat- one important example as these only form on surface
ing physiologically relevant shear stress values. The cor- bound sugars [40].
relation between ler1 expression and hydrodynamic force
clearly indicates that mechanical input regulates ler1 Identification of mechanosensitive systems ultimately
expression. These experiments constitute a unique and requires precise characterization of input-output rela-
exciting demonstration of transcriptional regulation mod- tionships. Techniques allowing generation and mea-
ulated by fluid flow. surements of minute forces and displacements have
been instrumental in characterizing mechanotransduc-
In this system, mechanotransmitting and mechanosen- tion in eukaryotic systems [2]. Optical tweezers, atomic
sing components have yet to be identified. Could the Cpx force microscopes and microfluidics are techniques that
system be involved? In the study mentioned in the hold promise to precisely characterize bacterial
previous section, Shimizu et al. demonstrated that EHEC mechanotransduction. These experiments will also pro-
upregulated type III secretion components encoded in vide new insights into the onset of pathogenicity,
LEE upon contact with hydrophobic surfaces [34 ]. They potentially opening novel routes for combatting infec-
showed that mutants in the NlpE-Cpx system were tious diseases.
surface-blind, indicating that NlpE also senses surfaces
to regulate EHEC virulence [32]. Shimizu and co-work- Acknowledgements
I would like to thank the editors of this special issue, Petra Dersch and
ers further demonstrated that transcriptional mechanor-
Michael Laub, for inviting me to write this essay. I also thank Joanne Engel
esponse was dependent on the Lrha transcription factor.
and Tom Silhavy for their comments on the manuscript. This work is
Lrha-dependent regulation may overlap with the GrlA supported by the Swiss National Science Foundation [grant number
31003A_169377].
system involved in host cell contact- and flow-dependent
regulation described by the Krachler group as both acti-
References and recommended reading
vate the master regulator Ler [35]. Bridging these two
Papers of particular interest, published within the period of review,
studies will help determine whether the NlpE-Cpx sys- have been highlighted as:
tem constitutes a clear mechanosensory component for
of special interest
contact and flow-dependent regulation of EHEC patho-
of outstanding interest
genicity.
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