ANRV255-CB21-14 ARI 1 September 2005 13:7

Quorum Sensing:
Cell-to-Cell
Communication in Bacteria
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

Christopher M. Waters and Bonnie L. Bassler

Department of Molecular Biology, Princeton University, Princeton, New Jersey
08544-1014; emails: [email protected], [email protected]
by CAPES on 06/06/08. For personal use only.

Annu. Rev. Cell Dev. Biol. Key Words

2005. 21:319–46
autoinducer, quorum quenching, regulon
First published online as a
Review in Advance on
June 28, 2005
Abstract
The Annual Review of Bacteria communicate with one another using chemical signal
Cell and Developmental molecules. As in higher organisms, the information supplied by these
Biology is online at molecules is critical for synchronizing the activities of large groups of
http://cellbio.annualreviews.org
cells. In bacteria, chemical communication involves producing, re-
doi: 10.1146/ leasing, detecting, and responding to small hormone-like molecules
annurev.cellbio.21.012704.131001
termed autoinducers. This process, termed quorum sensing, allows
Copyright

c 2005 by bacteria to monitor the environment for other bacteria and to al-
Annual Reviews. All rights
reserved ter behavior on a population-wide scale in response to changes in
the number and/or species present in a community. Most quorum-
1081-0706/05/1110-
0319$20.00 sensing-controlled processes are unproductive when undertaken by
an individual bacterium acting alone but become beneficial when car-
ried out simultaneously by a large number of cells. Thus, quorum
sensing confuses the distinction between prokaryotes and eukaryotes
because it enables bacteria to act as multicellular organisms. This
review focuses on the architectures of bacterial chemical communi-
cation networks; how chemical information is integrated, processed,
and transduced to control gene expression; how intra- and inter-
species cell-cell communication is accomplished; and the intriguing
possibility of prokaryote-eukaryote cross-communication.

319
 ANRV255-CB21-14 ARI 1 September 2005 13:7

QUORUM SENSING
Contents Quorum-sensing bacteria produce and release
QUORUM SENSING . . . . . . . . . . . . . . 320 chemical signal molecules termed autoinduc-
Quorum Sensing in ers whose external concentration increases
Gram-Negative Bacteria . . . . . . . 320 as a function of increasing cell-population
Quorum Sensing in Gram-Positive density. Bacteria detect the accumulation of
Bacteria . . . . . . . . . . . . . . . . . . . . . . . 323 a minimal threshold stimulatory concentra-
QUORUM-SENSING NETWORK tion of these autoinducers and alter gene ex-
ARCHITECTURE . . . . . . . . . . . . . . 325 pression, and therefore behavior, in response.
Parallel Quorum-Sensing Circuits . 325 Using these signal-response systems, bac-
Quorum-Sensing Circuits teria synchronize particular behaviors on a
Arranged in Series . . . . . . . . . . . . . 327 population-wide scale and thus function as
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Competitive Quorum-Sensing multicellular organisms. Here, we describe

Circuits . . . . . . . . . . . . . . . . . . . . . . . 329 some well-characterized quorum-sensing sys-
Quorum-Sensing Circuits with tems with the aim of illustrating their sim-
On-Off Switches . . . . . . . . . . . . . . 330 ilarities and differences. We presume sim-
Quorum-Sensing Systems ilarities in these systems exist because the
Responsive to Host Cues . . . . . . 331 ability to communicate is fundamental to bac-
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GLOBAL CONTROL: teria. Differences in the systems likely exist

QUORUM-SENSING because each system has been optimized to
REGULONS . . . . . . . . . . . . . . . . . . . . 331 promote survival in the specialized niche in
INTERSPECIES which a particular species of bacteria resides.
COMMUNICATION AMONG Thus, the types of signals, receptors, mecha-
BACTERIA . . . . . . . . . . . . . . . . . . . . . . 332 nisms of signal transduction, and target out-
QUORUM QUENCHING . . . . . . . . . 333 puts of each quorum-sensing system reflect
Prokaryote-to-Prokaryote Quorum the unique biology carried out by a particular
Quenching . . . . . . . . . . . . . . . . . . . . 334 bacterial species.
Eukaryote-to-Prokaryote Quorum
Quenching . . . . . . . . . . . . . . . . . . . . 334
Biotechnological Applications of Quorum Sensing in Gram-Negative
Quorum Quenching . . . . . . . . . . . 335 Bacteria
EVOLUTION AND
The first described quorum-sensing system
MAINTENANCE OF
is that of the bioluminescent marine bac-
QUORUM SENSING IN
terium Vibrio fischeri, and it is considered
BACTERIA . . . . . . . . . . . . . . . . . . . . . . 335
the paradigm for quorum sensing in most
RHOMBOID: A SHARED
gram-negative bacteria (Nealson & Hastings
PROKARYOTIC AND
1979). V. fischeri colonizes the light organ
EUKARYOTIC CHEMICAL
of the Hawaiian squid Euprymna scolopes. In
COMMUNICATION
this organ, the bacteria grow to high cell
MECHANISM . . . . . . . . . . . . . . . . . . 337
density and induce the expression of genes
CONCLUSIONS . . . . . . . . . . . . . . . . . . . 338
required for bioluminescence. The squid
uses the light provided by the bacteria for
counterillumination to mask its shadow and
avoid predation (Visick et al. 2000). The
bacteria benefit because the light organ is
rich in nutrients and allows proliferation
in numbers unachievable in seawater. Two

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Figure 1
Quorum sensing in
Vibrio fischeri; a
LuxIR signaling
circuit. Red triangles
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indicate the
autoinducer that is
produced by LuxI.
OM, outer
membrane; IM,
inner membrane.

proteins, LuxI and LuxR, control expres- the signal. This creates a positive feedback
sion of the luciferase operon (luxICDABE) loop that causes the entire population to
required for light production (Figure 1). switch into “quorum-sensing mode” and
Quorum sensing: a
LuxI is the autoinducer synthase, which produce light. process of cell-cell
produces the acyl-homoserine lactone (AHL) A large number of other gram-negative communication in
autoinducer 3OC6-homoserine lactone proteobacteria possess LuxIR-type pro- bacteria
(Figure 2a and Eberhard et al. 1981, teins and communicate with AHL signals Autoinducers:
Engebrecht & Silverman 1984), and LuxR is (Manefield & Turner 2002). These systems small molecules
the cytoplasmic autoinducer receptor/DNA- are used predominantly for intraspecies secreted by bacteria
that are used to
binding transcriptional activator (Engebrecht communication as extreme specificity exists
measure population
et al. 1983). Following production, the AHL between the LuxR proteins and their cog- density
freely diffuses in and out of the cell and nate AHL signals. LuxI-type proteins link
AHL:
increases in concentration with increasing and lactonize the methionine moiety from acyl-homoserine
cell density (Kaplan & Greenberg 1985). S-adenosylmethionine (SAM) to particular lactone
When the signal reaches a critical, threshold fatty acyl chains carried on acyl-acyl carrier SAM: S-adenosyl-
concentration, it is bound by LuxR and this proteins (More et al. 1996, Parsek et al. methionine
complex activates transcription of the operon 1999). A diverse set of fatty acyl side chains
encoding luciferase (Stevens et al. 1994). of varying length, backbone saturation, and
Importantly, the LuxR-AHL complex also in- side-chain substitutions are incorporated into
duces expression of luxI because it is encoded AHL signals; these differences are crucial
in the luciferase operon. This regulatory for signaling specificity (Figure 2a and
configuration floods the environment with Fuqua 1999). Structural studies of LuxI-type

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Figure 2
Representative bacterial autoinducers. The asterisk above the tryptophan in ComX represents an
isoprenyl modification.

proteins indicate that each possesses an acyl- AHLs, although it is not clear if all are
binding pocket that precisely fits a particular biologically relevant (Marketon et al. 2002).
side-chain moiety (Gould et al. 2004, Watson The structures of LuxR proteins suggest
et al. 2002). This structural feature apparently that LuxR proteins also possess specific acyl-
confers specificity in signal production. Thus, binding pockets that allow each LuxR to bind
each LuxI protein produces the correct signal and be activated only by its cognate signal
molecule with high fidelity. There are some (Vannini et al. 2002, Zhang et al. 2002b).
LuxI-type proteins that produce multiple Hence, it appears that in mixed-species

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environments in which multiple AHL signals mediated by a phosphorylation cascade that

are present, each species can distinguish, influences the activity of a DNA-binding tran-
measure, and respond only to the buildup of scriptional regulatory protein termed a re-
its own signal. Importantly, bacteria rarely sponse regulator. Similar to the mechanisms
rely exclusively on one LuxIR quorum- by which gram-negative bacteria use LuxIR
sensing system. Rather, bacteria use one or quorum-sensing systems, each gram-positive
more LuxIR systems, often in conjunction bacterium uses a signal different from that
with other types of quorum-sensing circuits. used by other bacteria and the cognate re-
Mechanisms must exist to prevent pre- ceptors are exquisitely sensitive to the sig-
mature activation of LuxIR-type quorum- nals’ structures. Thus, as in LuxIR systems,
sensing circuits because both the signal and peptide quorum-sensing circuits are under-
the detector are synthesized and interact in the stood to confer intraspecies communication.
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

cytoplasm (Figure 1). One such mechanism, Peptide signals are not diffusible across the
evidenced by the LuxR homologue TraR in membrane, hence signal release is mediated
the plant pathogen Agrobacterium tumefaciens, by dedicated oligopeptide exporters. In most
is the stability of LuxR-type proteins increases cases, concomitant with signal release is signal
upon AI binding. In the absence of autoin- processing and modification. While the bio-
ducer, TraR has a half-life of a few minutes. chemistry underlying these events is poorly
by CAPES on 06/06/08. For personal use only.

However, in the presence of AHL, the half- defined, it is known that most peptide
life of TraR increases to over 30 minutes (Zhu quorum-sensing signals are cleaved from
& Winans 1999). The crystal structure of larger precursor peptides, which then are
TraR predicts that AHL binding is required modified to contain lactone and thiolac-
for folding of the nascent polypeptide (Zhang tone rings, lanthionines, and isoprenyl groups
et al. 2002b), and indeed radiolabeled TraR (Ansaldi et al. 2002, Booth et al. 1996,
was stabilized only when its cognate AHL Mayville et al. 1999, Nakayama et al. 2001).
was added prior to labeling of the protein Many gram-positive bacteria communicate
(Zhu & Winans 2001). Hence, only when with multiple peptides in combination with
AHL accumulates to a significant concentra- other types of quorum-sensing signals.
tion (both outside and inside the cell) can A fascinating example of peptide quorum
TraR bind it, fold, and initiate the quorum- sensing exists in Staphylococcus aureus, which
sensing cascade. Another mechanism that pre- is normally a benign human commensal but
vents “short-circuiting” of LuxIR systems is becomes a deadly pathogen upon penetra-
active export of AHL signals (Pearson et al. tion into host tissues (reviewed in Tenover &
1999). When a significant concentration of Gaynes 2000). S. aureus uses a biphasic strat-
signal has accumulated, which is indicative of egy to cause disease: At low cell density, the
high cell density, diffusion into the cell over- bacteria express protein factors that promote
whelms export and thus engages the circuit. attachment and colonization, whereas at high
AHLs with long acyl side chains are thought cell density, the bacteria repress these traits
to require active export to transverse the bac- and initiate secretion of toxins and proteases
terial membrane (Pearson et al. 1999). that are presumably required for dissemina-
tion (reviewed in Lyon & Novick 2004). This
switch in gene expression programs is reg-
Quorum Sensing in Gram-Positive ulated by the Agr quorum-sensing system
Bacteria (Figure 3). The system consists of an autoin-
Gram-positive bacteria communicate using ducing peptide of Staphylococcus aureus (AIP)
modified oligopeptides as signals and “two- (Figure 2b) encoded by agrD (Ji et al. 1995)
component”-type membrane-bound sensor and a two-component sensor kinase-response
histidine kinases as receptors. Signaling is regulator pair, AgrC and AgrA, respectively

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 ANRV255-CB21-14 ARI 1 September 2005 13:7

Figure 3
Using a
two-component
response
regulatory system,
Staphylococcus
aureus detects and
responds to an
extracellular
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peptide. Small red

circles indicate the
AIP. P2 and P3
designate the
promoters for
agrBDCA and
RNAIII,
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respectively.

(Novick et al. 1995). The AgrB protein ex- reus groups results in intraspecies competi-
ports and adds the thiolactone ring modifi- tion; the S. aureus group that first establishes
cation to S. aureus AIPs (Saenz et al. 2000). its quorum-sensing cascade outcompetes the
AIP: autoinducing
peptide of Binding of the AIP to AgrC leads to phos- other group. Consistent with this idea, puri-
Staphylococcus aureus phorylation of AgrA. Phospho-AgrA induces fied AIP II attenuates virulence of a Group I
the expression of a regulatory RNA termed S. aureus in a mouse infection model (Mayville
RNAIII, which represses expression of cell- et al. 1999). Thus, in S. aureus, quorum sens-
adhesion factors while inducing expression of ing allows dissemination of closely related
secreted factors (Novick et al. 1993). Activated progeny while inhibiting the spread of non-
AgrA also induces expression of the agrBDCA. kin. Clinical analyses show that each S. au-
This results in increased AIP levels, which en- reus group is the primary causative agent of
sures that the entire population switches from a specific type of S. aureus disease. This sug-
the low-cell-density to the high-cell-density gests that cell-cell communication has been
state (Novick et al. 1995). instrumental in establishing a specific niche
S. aureus strains are classified on the ba- for each “strain” (Novick 2003). The codiver-
sis of the sequence of their thiolactone- gence of the signal-receptor pairs occurring
containing AIP. At present, four different AIPs in these bacteria may be one molecular mech-
(Figure 2b and Dufour et al. 2002), and thus anism underlying the evolution of new bacte-
four different groups of S. aureus, are known. rial species.
Surprisingly, each AIP specifically activates its Streptomycetes are a diverse family of
cognate AgrC receptor but inhibits activation gram-positive soil-dwelling bacteria that are
of all others by competitive binding to the of clinical relevance because they are a ma-
non-cognate receptors (Lyon et al. 2002b). jor biological reservoir of secondary metabo-
Thus, each AIP inhibits activation of the vir- lites, many of which are used as antibi-
ulence cascade in the other three groups of otics (reviewed in Chater & Horinouchi
S. aureus while not affecting the other groups’ 2003). Streptomycetes use γ -butyrolactones
growth. Coinfection with two different S. au- (Figure 2c) as autoinducers and control

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morphological differentiation and secondary

metabolite production via quorum sensing. CHEMICAL COMPLEXITY IN BACTERIAL
Their signals are intriguing because they AUTOINDUCERS
are structurally related to AHL autoinduc-
Recent research shows that a rich diversity of chemical
ers. However, there has not yet been any re-
molecules is used for communication in the bacterial world.
port describing either cross-communication
New genetic, biochemical, and imaging techniques have en-
between or cross-inhibition of streptomycetes
hanced our ability to identify and measure the readouts of
and Gram-negative bacteria that communi-
cell-cell communication. These tools have led to the identifi-
cate with AHLs.
cation of several novel molecules and classes of molecules that
are clearly bona fide autoinducers mediating cell-cell commu-
QUORUM-SENSING NETWORK nication. A few examples are
ARCHITECTURE PQS The molecule 3,4-dihydroxy-2-heptylquinoline,
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

Identification of the chemical signals, recep- termed PQS, is a signal that is integral to the P. aeruginosa
tors, target genes, and mechanisms of signal quorum-sensing cascade (Pesci et al. 1999). This signal acts
transduction involved in quorum sensing is as an additional regulatory link between the Las and Rhl
leading to a comprehensive understanding of quorum-sensing circuits.
cell-cell communication in bacteria. This re- 3OH PAME 3OH palmitic acid methyl ester (3OH
search is providing insight into the variety of PAME) transmits information via the two-component sensor
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molecular arrangements that enable commu- histidine kinase-response regulator pair, PhcS-PhcR, to cause
nication between cells as well as the unique the plant pathogen Ralstonia solanacearum to switch from a
characteristics that the various signaling ar- motile to an infective state (Flavier et al. 1997).
chitectures provide in terms of information CYCLIC DIPEPTIDES Newly described in a num-
dissemination, detection, relay, and response. ber of gram-negative bacteria, at high concentrations, cyclic-
Below we highlight a few quorum-sensing dipeptides antagonize AHL binding to cognate receptors
systems and discuss how each particular net- (Holden et al. 1999).
work arrangement leads to distinct signaling
features.
dine kinase (LuxN) similar to sensors in
Parallel Quorum-Sensing Circuits Gram-positive quorum-sensing signaling cir-
The first observation that bacteria could com- cuits (Bassler et al. 1993, Freeman et al. 2000).
municate with multiple quorum-sensing sig- The second V. harveyi signal is a furanosyl
nals was in the quorum-sensing system of the borate diester known as AI-2 (Figure 2d
Gram-negative, bioluminescent marine bac- and Bassler et al. 1994a, Chen et al. 2002),
terium Vibrio harveyi (Figure 4). The V. har- production of which requires the LuxS en-
veyi quorum-sensing system consists of three zyme (Surette et al. 1999, Xavier & Bassler
autoinducers and three cognate receptors 2003). AI-2 is bound in the periplasm by the
functioning in parallel to channel informa- protein LuxP; the LuxP-AI-2 complex inter-
tion into a shared regulatory pathway. Sim- acts with another membrane-bound sensor
ilar to other Gram-negative bacteria, V. har- histidine kinase, LuxQ (Bassler et al. 1994a).
veyi produces an AHL signal termed HAI-1 The third V. harveyi signal, an unidentified
(3OHC4-homoserine lactone; Figure 2a and molecule termed CAI-1, is produced by the
Cao & Meighen 1989). Its synthase, LuxM, CqsA enzyme, and again, this signal interacts
shares no homology to LuxI-type enzymes with a membrane-bound sensor histidine ki-
but catalyzes the identical biochemical re- nase, CqsS (Henke & Bassler 2004b).
action to generate a specific AHL (Bassler At low cell density, in the absence of ap-
et al. 1993, Hanzelka et al. 1999). HAI-1 preciable amounts of autoinducers, the three
binds to a membrane-bound sensor histi- sensors—LuxN, LuxQ, and CqsA—act as

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Figure 4
Vibrio harveyi produces and responds to three distinct autoinducers. The sensory information is fed into
a shared two-component response regulatory pathway. The arrows indicate the direction of phosphate
flow in the low-cell-density state. CAI-1, HAI-1, and AI-2 are respectively represented by green circles,
red triangles, and blue double pentagons. OM, outer membrane; IM, inner membrane.

kinases, autophosphorylate, and subsequently volved in mRNA splicing (Carrington &

transfer the phosphate to the cytoplasmic Ambros 2003). The sRNAs, together with
protein LuxU (Figure 4). LuxU passes the Hfq, bind to and destabilize the mRNA en-
sRNAs: small RNAs
phosphate to the DNA-binding response reg- coding the transcriptional activator termed
ulator protein LuxO (Bassler et al. 1994b, LuxR (not similar to LuxR of V. fischeri) (Lenz
Freeman & Bassler 1999a,b, Freeman et al. et al. 2004). LuxR is required to activate
2000). Phospho-LuxO, in conjunction with transcription of the luciferase operon luxCD-
a transcription factor termed σ 54 , activates ABE (Swartzman et al. 1992). Thus, at low cell
transcription of the genes encoding five reg- density, because the luxR mRNA is degraded,
ulatory small RNAs (sRNAs) termed Qrr1– the bacteria do not express bioluminescence.
5 (for Quorum Regulatory RNA) (Lilley & At high cell density, when the autoinducers ac-
Bassler 2000, Lenz et al. 2004). The Qrr cumulate to the level required for detection,
sRNAs interact with an RNA chaperone the three sensors switch from being kinases to
termed Hfq, which is a member of the Sm being phosphatases and drain phosphate from
family of eukaryotic RNA chaperones in- LuxO via LuxU. Unphosphorylated LuxO

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cannot induce expression of the sRNAs. This promotes light production, as described above
allows translation of luxR mRNA, production (Fidopiastis et al. 2002). This latter event oc-
of LuxR, and expression of bioluminescence. curs at relatively high cell densities, which
This pathway controls many genes in addition presumably can be achieved only in the squid
to those encoding luciferase (Henke & Bassler and cannot be achieved in the open ocean.
2004a, Mok et al. 2003). These three vibrio quorum-sensing
The human pathogen Vibrio cholerae, the systems underscore the way in which a
causative agent of the endemic diarrheal dis- common quorum-sensing network can be
ease cholera, possesses a quorum-sensing net- modified to fit the unique biology of the
work similar to that of V. harveyi (Miller et al. bacteria. Whereas the two-tiered V. fischeri
2002). V. cholerae has no equivalent to the AI- circuit is adapted for two disparate lifestyles,
1/LuxN branch of the system. However, this inside and outside of the squid, V. harveyi and
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bacterium does possess the AI-2/LuxPQ and V. cholerae do not possess LuxIR homologues
CAI-1/CqsS branches as well as LuxU, LuxO, and they are not known to exist in symbiotic
four Qrr sRNAs, and a V. harveyi LuxR-like relationships. Although V. harveyi and V.
protein termed HapR. The V. cholerae sys- cholerae share many of the same signals and
tems function analogously to those of V. har- receptors, the relative input from each signal
veyi but control virulence instead of regu- is different in the two species. CqsA/CqsS is
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lating bioluminescence (Miller et al. 2002, the dominant signaling-circuit in V. cholerae

Zhu et al. 2002). Surprisingly, quorum sensing whereas it is the weakest in V. harveyi (Henke
promotes V. cholerae virulence factor expres- & Bassler 2004b). These signaling variations,
sion and biofilm formation at low cell density coupled with their regulation of distinct
and represses these traits at high cell density downstream virulence factors, may be deter-
(Hammer & Bassler 2003). Quorum sensing mining factors that allow V. cholerae, but not
commonly controls bacterial virulence fac- V. harveyi, to infect humans.
tor expression, but typically, induction occurs In each vibrio circuit, all signal-receptor
at high cell density. This opposite regulatory pairs channel phosphate to LuxO in the ab-
pattern exhibited by V. cholerae can be under- sence of a signal and remove phosphate from
stood in terms of the specific disease that the LuxO in the presence of a signal. Thus, be-
bacterium causes. Following a successful V. cause all signals lead to a reduction in the
cholerae infection, the ensuing diarrhea wash level of LuxO-phosphate, each signal rein-
huge numbers of bacteria from the human in- forces the information encoded in the other
testine into the environment. Repression of signals. This arrangement may allow the net-
virulence factor production and biofilm for- work to function as a coincidence detector
mation genes at high cell density may promote that significantly activates or represses gene
dissemination of V. cholerae. expression only when all signals are simulta-
Upon the recent completion of the V. fis- neously present or absent (Mok et al. 2003).
cheri genome sequence, it was revealed that, This signaling architecture may be critical for
in addition to LuxIR, homologues of two of filtering out noise from molecules in the en-
the V. harveyi quorum-sensing circuits and the vironment that are related to the true signals
shared downstream components are present: and/or noise from signal mimics produced by
LuxMN, LuxSPQ, LuxU, LuxO, and LuxR other bacteria in the vicinity.
(referred to as LitR in V. fischeri) (Fidopiastis
et al. 2002, Lupp & Ruby 2004, Lupp et al.
2003, Miyamoto et al. 2003). In V. fischeri, the Quorum-Sensing Circuits Arranged
V. harveyi-like quorum-sensing systems acti- in Series
vate expression of litR at low cell densities. As in the vibrios, the Pseudomonas aerugi-
LitR induces expression of luxR, which in turn nosa quorum-sensing circuit is responsive to

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Figure 5
The Pseudomonas
aeruginosa
quorum-sensing
circuits operate in
series to control a
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large set of target

genes. The LasI
autoinducer is
represented by red
triangles and the
RhlI autoinducer is
shown as blue
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triangles. OM,
outer membrane;
IM, inner
membrane.

multiple autoinducers, however, unlike those positive feedback loop that further activates
in vibrios, the P. aeruginosa regulatory sys- the system (Figure 5 and Seed et al. 1995).
tems are arranged in series rather than in The LasR-autoinducer complex also activates
CF: cystic fibrosis
parallel. P. aeruginosa, a common soil organ- the expression of rhlR and rhlI encoding an-
ism, is also an opportunistic pathogen most other quorum-sensing circuit. RhlI produces
notorious for its devastating effects on cys- the AHL C4-homoserine lactone (Figure 2a
tic fibrosis (CF) patients (Eberl & Tummler and Pearson et al. 1995). Following accumu-
2004). Quorum sensing is essential for chronic lation, RhlR binds the RhlI-directed signal;
P. aeruginosa respiratory infection because it this complex activates its own set of target
controls adhesion, biofilm formation, and vir- genes. Importantly, because the LasIR sys-
ulence factor expression, all of which al- tem induces both rhlI and rhlR, induction of
low persistence in the lung and are required the genes under RhlIR control occurs sub-
for disease progression (Smith & Iglewski sequent to induction of genes under LasIR
2003). control.
The P. aeruginosa quorum-sensing net- Microarray analyses of P. aeruginosa
work consists of two LuxIR circuits, termed quorum-sensing-controlled gene expression
LasIR and RhlIR (Figure 5 and Gambello revealed three classes of genes: genes that re-
& Iglewski 1991, Ochsner et al. 1994). spond to only one autoinducer, genes that re-
LasI, a LuxI homologue, produces an AHL spond to either autoinducer, and genes that
autoinducer (3OC12-homoserine lactone; require both autoinducers simultaneously for
Figure 2a and Pearson et al. 1994) that activation (Hentzer et al. 2003; Schuster et al.
binds to LasR. The LasR-autoinducer com- 2003; Wagner et al. 2003, 2004). Further-
plex activates a variety of target genes in- more, transcriptome analyses showed that
cluding lasI, which sets up the characteristic these classes of genes are expressed at different

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 ANRV255-CB21-14 ARI 1 September 2005 13:7

times over the growth cycle. This indicates ment that allows B. subtilis to commit to one of
that the tandem network architecture indeed two mutually exclusive lifestyles: competence
produces a temporally ordered sequence of (the ability to take up exogenous DNA) and
gene expression that may be critical for the sporulation (Figure 6). ComX, a 10-amino
ordering of early and late events in a success- acid peptide (Figure 2b and Magnuson et al.
ful infection (Schuster et al. 2003, Whiteley 1994, Solomon et al. 1996) that is processed
et al. 1999). and secreted by ComQ (Bacon Schneider et al.
2002), is detected by the membrane-bound
histidine sensor kinase ComP. ComX bind-
Competitive Quorum-Sensing ing stimulates ComP to autophosphorylate
Circuits and transfer phosphate to the DNA-binding
The above quorum-sensing networks rely on response regulator ComA (Solomon et al.
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

multiple signals acting synergistically. Other 1995). Phosphorylated ComA regulates tran-
quorum-sensing networks are arranged such scription of a variety of genes encoding fac-
that the signals antagonize one another. For tors required for competence development
example, Bacillus subtilis has two autoinducing (Nakano & Zuber 1991). A second oligopep-
peptides functioning in a network arrange- tide autoinducer, competence and sporulation
by CAPES on 06/06/08. For personal use only.

Figure 6
Bacillus subtilis produces two autoinducing peptides that regulate two different developmental pathways:
competence and sporulation. ComX is represented as a chain of purple ovals and CSF is shown as a chain
of red ovals.

www.annualreviews.org • Cell-to-Cell Communication in Bacteria 329

 ANRV255-CB21-14 ARI 1 September 2005 13:7

factor of B. subtilis (CSF; encoded by the for sporulation (Grossman 1995, Perego
gene phrC), is released via the general secre- 1997).
tory apparatus, is re-internalized through the
CSF: competence
and sporulation Opp peptide transporter, and acts in the cy-
toplasm (Figure 2b; Figure 6; and Lazazzera Quorum-Sensing Circuits with
factor of B. subtilis
et al. 1997, Solomon et al. 1996). At low in- On-Off Switches
CSP: competence-
stimulating peptide ternal concentrations, CSF binds to a pro- The above quorum-sensing circuits allow bac-
of S. pneumoniae tein named RapC and disrupts RapC bind- teria to transition from a set of low cell density
ing to ComA (Perego 1997, Solomon et al. behaviors to a different set of high cell den-
1996). RapC binding to ComA inhibits com- sity behaviors. There are, however, quorum-
petence development because DNA binding sensing circuits that promote transient expres-
by ComA is prevented. Thus, CSF bind- sion of particular traits followed by reversion
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

ing to RapC promotes competence devel- to the original set of behaviors. Such an on-
opment (Core & Perego 2003). However, off switch controls competence development
at high concentrations, internalized CSF in- in the Gram-positive bacterium Streptococ-
hibits the ComP-ComA signaling cascade cus pneumoniae, which uses an oligopeptide
through an unknown mechanism, decreas- autoinducer named competence-stimulating
ing competence development and favoring peptide (CSP) to monitor cell density (Fig-
by CAPES on 06/06/08. For personal use only.

sporulation (Lazazzera et al. 1997, Solomon ure 2b). CSP is encoded by comC (Havarstein
et al. 1996). CSF also directly promotes et al. 1995, Tomasz & Hotchkiss 1964).
sporulation by inhibiting RapB-mediated de- The transporter ComAB exports and modi-
phosphorylation of a response regulator fies CSP (Hui et al. 1995). CSP is detected by
named Spo0F, which, in its phosphory- the membrane-bound sensor histidine kinase
lated state, indirectly activates genes required ComD, which transfers phosphate to the cy-
toplasmic response regulator ComE (Pestova
et al. 1996). This circuit controls the tran-
scription of gene subsets in a precise tempo-
ral order. Early genes are expressed maximally
6–7 min after CSP accumulation; late genes
are maximally induced at 9–10 min (Peter-
son et al. 2000). ComE directly activates tran-
scription of early genes that include comAB
and comCDE; this causes increased signal pro-
duction and detection (Pestova et al. 1996).
This positive feedback loop results in a dra-
matic, population-wide spike in competence
when the bacteria reach the critical cell den-
sity (Figure 7). ComE also activates tran-
scription of comX, a gene encoding an alter-
nate sigma factor (Lee & Morrison 1999),
and comW, which is required for transcription
of late genes encoding proteins essential for
DNA uptake (Luo et al. 2004).
A novel feature of S. pneumoniae quorum-
Figure 7
sensing circuit is the rapidity with which
Competence in Streptococcus pneumoniae (red line) rises sharply at a specific
growth stage (blue line), followed by a rapid decline. Optical Density the process of competence development ini-
(OD550) was used to measure cell number and resistance to erythromycin tiates and terminates (Figure 7 and Tomasz
(Ery-R) was used to assess competence. Figure courtesy of D. Morrison. & Hotchkiss 1964). Importantly, competent

330 Waters · Bassler

 ANRV255-CB21-14 ARI 1 September 2005 13:7

S. pneumoniae cells are more prone to autolysis GLOBAL CONTROL:

than are noncompetent cells (Dagkessaman- QUORUM-SENSING REGULONS
skaia et al. 2004, Morrison & Baker 1979, Seto
The advent of genomic profiling has shown TI: tumor-inducing
& Tomasz 1975, Steinmoen et al. 2003). Thus,
that quorum sensing, in many bacteria, con- Regulon: a set of
the benefit gained from acquiring DNA that
trols gene expression in a global manner. genes under
can be used as a repository of new genes is common regulatory
Two transcription profiling studies identi-
maximized by efficiently activating and ter- control
fied over 150 competence-regulated genes
minating the process to minimize lethality by
in S. pneumoniae that were categorized as
autolysis. The events leading to termination
early, late, delayed-induction, and repressed
have not been defined. It is known that ComX
(Dagkessamanskaia et al. 2004, Peterson et al.
rapidly disappears when competence is termi-
2004). As previously mentioned, early genes
nated, which suggests that regulated proteol-
are required for signal production, export,
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

ysis occurs (Luo et al. 2004).

and detection whereas some late genes are
necessary for DNA internalization. Many of
Quorum-Sensing Systems the delayed genes are involved in bacte-
Responsive to Host Cues rial stress responses (Dagkessamanskaia et al.
2004, Peterson et al. 2004). Gene-disruption
Agrobacterium tumefaciens induces crown gall
experiments analyzing 124 quorum-sensing-
by CAPES on 06/06/08. For personal use only.

tumors in plants through transfer and inte-

controlled genes found that only 23 are re-
gration of a tumor-inducing (TI) plasmid into
quired for competence (Peterson et al. 2004).
plant cells (Zhu et al. 2000). The tumors pro-
Quorum-sensing mutants of S. pneumoniae
duce molecules termed opines, which the bac-
and related streptococci show defects in mul-
teria use as nutrients (Dessaux et al. 1992).
tiple pathways, including biofilm formation,
The quorum-sensing circuit of A. tumefaciens
acid tolerance, bacteriocin production, and
is especially interesting because it is only ac-
virulence (reviewed in Suntharalingam &
tivated at the host-bacterial interface owing
Cvitkovitch 2005). Together, these results
to a requirement for both plant- and bacteria-
suggest that quorum sensing in streptococ-
produced signals. Mobilization of the TI plas-
cus controls the initiation of a global devel-
mid is responsive to proximity to the plant
opmental program in which competence de-
because it requires detection of opines by a
velopment represents only one aspect.
cytoplasmic receptor termed AccR or OccR
Further evidence that quorum sensing co-
(Beck von Bodman et al. 1992, Fuqua &
ordinates the control of a large subset of
Winans 1994). AccR/OccR-opine binding in-
genes comes from transcriptome analyses of P.
duces expression of the V. fischeri-like luxR ho-
aeruginosa that identify 616 genes as part of the
mologue, traR (Fuqua & Winans 1994). TraR
regulon. In one study, addition of autoinduc-
responds to an AHL autoinducer produced by
ers repressed 222 genes (Wagner et al. 2003).
the V. fischeri LuxI-type enzyme, TraI (Hwang
A concurrent study identified 315 quorum-
et al. 1994, Zhang et al. 1993). Hence, bacte-
sensing-controlled targets, of which only 38
rial number controls TI transfer because TraR
were repressed (Schuster et al. 2003). Al-
bound to its autoinducer induces TI plas-
though the two experiments were performed
mid replication and bacterial-bacterial conju-
under different growth and autoinducer con-
gation, which lead to increased infectivity of
ditions, the reasons for the discrepancies re-
the population (Zhu & Winans 1999). Anti-
main unclear. Importantly, prior to these
TraR activators exist that limit TraR activ-
profiling analyses, quorum-sensing-repressed
ity and thus presumably optimize the ratio of
targets had not been identified in P. aerugi-
bacteria-bacteria to bacterial-plant TI trans-
nosa. Similarly, transcriptional analysis of V.
fer (Chai et al. 2001, Fuqua et al. 1995, Hwang
cholerae quorum-sensing mutants shows that
et al. 1995).

www.annualreviews.org • Cell-to-Cell Communication in Bacteria 331

 ANRV255-CB21-14 ARI 1 September 2005 13:7

the entire virulence regulon (>70 genes) is re- moiety to various substrates produces the
pressed by quorum sensing (Zhu et al. 2002). toxic byproduct S-adenosylhomocysteine
These recent whole-genome quorum- (SAH) (Schauder et al. 2001). In non-LuxS-
SAH: S-adenosyl-
homocysteine sensing studies highlight two important ideas. containing bacteria and eukaryotes, the
First, quorum sensing allows bacteria to al- enzyme SAH hydrolase metabolizes SAH
DPD:
4,5-dihydroxy-2,3- ternate between distinct genome-wide pro- to adenosine and homocysteine. However,
pentonedione, a grams. These findings, along with an en- in bacteria containing LuxS, two enzymes,
molecule generated hanced appreciation of the complexity of Pfs and LuxS, act sequentially to convert
by LuxS the quorum-sensing network architectures, SAH to adenine, homocysteine, and the
have fundamentally changed the perception signaling molecule DPD (Figure 8 and
of bacteria as primitive single-celled organ- Schauder et al. 2001). DPD is a highly
isms. Bacteria now are understood to undergo reactive product that can rearrange and
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

complex programs of development similar in undergo additional reactions, which suggests

many respects to eukaryotic organisms. Sec- that distinct but related molecules derived
ond, large groups of genes are repressed by from DPD may be the signals that different
quorum sensing. This finding challenges the bacterial species recognize as AI-2. Two
notion that the primary function of quorum distinct DPD-derived signals were identified
sensing is to initiate activities that are only in V. harveyi and Salmonella typhimurium
by CAPES on 06/06/08. For personal use only.

beneficial to bacterial participation in group by trapping the active molecules in their

activities. Rather, an equally important func- respective receptors (LuxP for V. harveyi and
tion of quorum sensing may be to terminate LsrB for S. typhimurium), crystallizing the
processes that are only beneficial to bacteria complexes, and solving their structures (Chen
living in relative isolation outside of a com- et al. 2002, Miller et al. 2004, Taga et al.
munity structure. 2001). In V. harveyi, AI-2 is (2S,4S)-2-methyl-
2,3,3,4-tetrahydroxytetrahydrofuran-borate
(S-THMF borate); in S. typhimurium, AI-2
INTERSPECIES is (2R,4S)-2-methyl-2,3,3,4-tetrahydroxyte-
COMMUNICATION AMONG trahydrofuran (R-THMF) (Figure 2d and
BACTERIA Figure 8). Straightforward chemistry links
Beyond controlling gene expression on a these two molecules, as DPD can cyclize
global scale, quorum sensing allows bacteria with two equally feasible stereochemistries.
to communicate within and between species. Following hydration and borate addition,
This notion arose with the discovery and study the upper cyclization pathway in Figure 8
of the autoinducer AI-2, which is one of sev- yields the V. harveyi AI-2 and the lower
eral signals used by V. harveyi in quorum sens- cyclization and hydration pathway yields the
ing (Figure 2d and Figure 4). Specifically, S. typhimurium AI-2.
luxS encoding the AI-2 synthase is present Identification of boron in V. harveyi AI-2
in roughly half of all sequenced bacterial is surprising, as few biological roles for boron
genomes, AI-2 production has been verified are known. However, boron is present in high
in a large number of these species, and AI-2 concentrations (∼0.4 mM) in the marine en-
controls gene expression in a variety of bac- vironment, which makes it a reasonable el-
teria. Together, these findings have led to the ement in the V. harveyi AI-2 signal (Bowen
hypothesis that bacteria use AI-2 to commu- 1966). Significantly lower boron concentra-
nicate between species (reviewed in Xavier & tion is found in terrestrial environments. This
Bassler 2003). makes boron an unlikely component of the S.
LuxS functions in the pathway for typhimurium AI-2 signal (Fresenius 1988). Im-
metabolism of SAM, the major cellular portantly, all of the chemical species shown
methyl donor. Transfer of the methyl in Figure 8 exist in equilibrium and rapidly

332 Waters · Bassler

 ANRV255-CB21-14 ARI 1 September 2005 13:7
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

Figure 8
AI-2 is a family of interconverting molecules derived from DPD. Vibrio harveyi AI-2 is S-THMF-borate
and Salmonella typhimurium AI-2 is R-THMF. Figure from Miller et al. 2004.
by CAPES on 06/06/08. For personal use only.

interconvert. Moreover, the concentrations nal molecules, this pathway may represent an
of each molecule can be altered by manip- especially economical method for evolving a
ulating the boron concentration. For exam- complex bacterial lexicon.
ple, addition of boron to DPD preparations
promotes formation of the V. harveyi AI-2
molecule at the expense of the S. typhimurium QUORUM QUENCHING
signal. This shift is biologically relevant be- The fundamental role of quorum sensing ap-
cause DPD supplemented with boron causes pears to be global control of the physiology
V. harveyi to produce maximal biolumines- of bacterial populations. This control is often
cence whereas the same mixture inhibits the exerted at the interface of different bacterial
AI-2 response from S. typhimurium. Con- populations or at the bacterial-host margin. In
versely, DPD preparations depleted for boron niches in which bacterial populations compete
promote formation of the S. typhimurium sig- for limited resources, the ability to disrupt
nal with the concomitant loss of the V. harveyi quorum sensing may give one bacterial species
AI-2. Again, this chemistry is borne out in the an advantage over another that relies on quo-
effect on AI-2-responsive gene expression in rum sensing. Likewise, a host’s ability to in-
the two bacterial species (Miller et al. 2004). terfere with bacterial cell-cell communication
These initial AI-2 investigations show may be crucial in preventing colonization by
that bacteria employ a conserved biosynthetic pathogenic bacteria that use quorum sensing
pathway to synthesize chemical signal inter- to coordinate virulence. Thus, it is not surpris-
mediates whose fates are ultimately defined by ing that mechanisms have evolved to interfere
the chemistry of the particular environment. with bacterial cell-cell communication in pro-
Other DPD derivatives may exist and be bi- cesses termed quorum quenching. Analogous
ologically active. Additionally, some bacteria mechanisms presumably exist for promoting
may possess two or more AI-2 receptors for quorum-sensing-controlled behaviors when
recognition of different derivatives of DPD such behaviors provide benefits to organisms
and alter particular behaviors in response to cohabitating with quorum-sensing bacteria.
the information conveyed by each signal. Be- These latter processes are not yet well defined,
cause only one enzyme (LuxS) is required to so we will focus our discussion primarily on
synthesize this family of interconverting sig- mechanisms of quorum quenching.

www.annualreviews.org • Cell-to-Cell Communication in Bacteria 333

 ANRV255-CB21-14 ARI 1 September 2005 13:7

Prokaryote-to-Prokaryote Quorum nates quorum-sensing activities. For exam-

Quenching ple, in stationary phase, A. tumefaciens pro-
duces the AttM AHL lactonase, which can
As mentioned, cross-inhibition of AIP-
degrade the A. tumefaciens autoinducer
mediated signaling in S. aureus represents a
(Zhang et al. 2002a). It is hypothesized that
clear example of a quorum-quenching mecha-
it is disadvantageous for A. tumefaciens to
nism because each of the four AIPs specifically
continue to participate in group activities at
inhibits quorum sensing in competing S. au-
this late growth stage and that AttM halts
reus groups while not disrupting growth and
these processes. Erwinia carotovora and Xan-
other cellular functions (Lyon et al. 2002a).
thomonas campestris show a similar loss of AHL
Many Bacillus species secrete an enzyme, AiiA,
in stationary phase growth, which suggests
that cleaves the lactone rings from the acyl
an autoinducer degradative activity (Barber
moieties of AHLs and renders the AHLs
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

et al. 1997, Holden et al. 1998). P. aerugi-

inactive in signal transduction (Dong et al.
nosa degrades long, but not short, chain AHLs
2000). AiiA is extremely nonspecific with
through an AiiD-type acylase named PvdQ
regard to the AHL acyl side chain, which
(Huang et al. 2003). In this case, the RhlI
suggests that this strategy interferes generi-
autoinducer, C4-homoserine lactone, is im-
cally with AHL-mediated communication be-
mune, and the LasI autoinducer, 3OC12-
tween gram-negative bacteria (Dong et al.
by CAPES on 06/06/08. For personal use only.

homoserine lactone, can be destroyed. In-

2001). Significantly, as previously mentioned,
terestingly, pvdQ is a member of the LasIR
Bacillus relies on oligopeptide-mediated quo-
regulon and it is thus under 3OC12-
rum sensing. Therefore, this tactic, while dis-
homoserine control (Huang et al. 2003,
rupting gram-negative bacterial communica-
Whiteley et al. 1999).
tion, leaves Bacillus cell-cell communication
Some enteric bacteria, including S. ty-
unperturbed.
phimurium and Escherichia coli, import AI-
The soil bacterium Variovorax para-
2 with an AI-2-specific transporter (Surette
doxus uses a different generalized anti-
et al. 1999; Taga et al 2001, 2003; Xavier &
AHL quorum-quenching tactic (Leadbetter
Bassler 2005). Once AI-2 is in the cytoplasm,
& Greenberg 2000). Like Bacillus, V. para-
a series of enzymatic reactions inactivates its
doxus also degrades AHLs. However, in this
signaling activity. This process reduces ex-
case, AHL destruction occurs via an acylase-
tracellular AI-2 concentrations to levels in-
mediated lactone ring opening. V. paradoxus
dicative of low cell density and—because AI-
uses the linearized product of the reaction as
2 is used for interspecies communication—
a source of carbon and nitrogen. This strat-
indicative of monospecies environments.
egy provides V. paradoxus with a double bene-
AI-2 internalization is suspected to be an-
fit: It terminates competitors’ group behaviors
other mechanism for interference with chem-
and simultaneously increases its own growth
ical communication among bacteria. Because
potential (Leadbetter & Greenberg 2000).
E. coli and S. typhimurium also produce AI-2
Particular Ralstonia isolates contain an AHL
and respond to this signal (Taga et al. 2001,
acylase encoded by aiiD, which suggests a sim-
2003), it is not clear how these bacteria regu-
ilar anti-quorum-sensing mechanism to that
late AI-2 import while protecting the fidelity
of V. paradoxus (Lin et al. 2003). The Ral-
of their own AI-2 signaling cascades.
stonia quorum-sensing system is immune be-
cause the Ralstonia autoinducer, 3OH-PAME
(Flavier et al. 1997), is not affected by AiiD Eukaryote-to-Prokaryote Quorum
activity (described in the sidebar). Quenching
In some cases, bacteria may degrade their
Several eukaryotic mechanisms that counter-
own autoinducers, which presumably termi-
act bacterial quorum sensing have recently

334 Waters · Bassler

 ANRV255-CB21-14 ARI 1 September 2005 13:7

been discovered. The Australian red macro- ized human epithelial cell lines show spe-
agla Delisea pulchra coats its surface with a cific inactivation of the P. aeruginosa 3OC12-
mixture of halogenated furanones that bear homoserine lactone autoinducer (the product
structural similarity to AHLs (Givskov et al. of LasI) but not of the C4-homoserine lac-
1996). The furanones are internalized by bac- tone autoinducer (the product of RhlI) (Chun
teria, bind to LuxR-type proteins, and cause et al. 2004). Although presently uncharacter-
the degradation of these proteins (Manefield ized, the quenching activity is membrane as-
et al. 2002). This strategy prevents bacte- sociated and heat liable, which suggests that it
rial colonization of the algal surface by in- is a protein. This activity is intriguing in terms
hibiting quorum-sensing-controlled biofilm of the development of anti-P. aeruginosa ther-
formation. apies for treatment of CF.
The legume Medicago truncatula controls
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

over 150 proteins in response to AHLs pro-

duced by two model quorum-sensing bacte- Biotechnological Applications of
ria; Sinorhizobium meliloti and P. aeruginosa Quorum Quenching
(Mathesius et al. 2003). The plant secretes Naturally occurring quorum-quenching pro-
compounds in response to AHLs. These fac- cesses are being tested as novel antimicrobial
tors inhibit AI-2 signaling and stimulate AHL therapies. Overexpression of aiiA in tobacco
by CAPES on 06/06/08. For personal use only.

signaling in quorum-sensing reporter strains. and potato plants confers resistance to E. caro-
The plant presumably encourages signaling tovora, which requires AHL-controlled viru-
between AHL-producing bacteria but not AI- lence factor expression to cause disease (Dong
2-producing bacteria because only the former et al. 2001). Likewise, coculture of Bacillus
are beneficial to the plant. Similarly, Pisum thuringiensis decreased E. carotovora–mediated
sativum (pea) produces AHL mimics that plant disease in an aiiA-dependent manner
both positively and negatively affect AHL- (Dong et al. 2004). Mice treated with syn-
regulated behaviors in a number of bacterial thetic antagonists of S. aureus AIP show resis-
reporter strains (Teplitski et al. 2000). tance to infection (Mayville et al. 1999). Sim-
Reactive oxygen and nitrogen intermedi- ilarly, purified halogenated furanones appear
ates generated by NADPH oxidase inacti- to attenuate virulence of bacteria in mouse
vate the S. aureus autoinducing peptide in a models (Hentzer et al. 2003, Wu et al. 2004).
mouse air pouch skin model (Rothfork et al. These and other examples predict that in-
2004). These findings indicate a novel role for hibition of quorum sensing offers an attrac-
NADPH oxidase, an important component of tive alternative to traditional antibiotics be-
innate immunity, in protection from bacterial cause these strategies are not bactericidal and
infections. Consistent with this, mice defi- the occurrence of bacterial resistance there-
cient in NADPH oxidase have reduced resis- fore could be reduced. Likewise, approaches
tance to infection by S. aureus, whereas infec- aimed at promoting beneficial quorum-
tion from quorum-sensing mutant S. aureus sensing associations may enhance industrial-
remains unaffected by the loss of NAPH oxi- scale production of natural or engineered
dase (Rothfork et al. 2004). This latter result bacterial products.
suggests that reactive oxygen species influence
infectivity only through quorum quenching.
The authors of this study speculate that ox- EVOLUTION AND
idation of other kinds of quorum-sensing MAINTENANCE OF QUORUM
molecules by NADPH oxidase is likely SENSING IN BACTERIA
(Rothfork et al. 2004). Quorum sensing presumably provides bacte-
Human cells also have quorum-quenching ria benefits from group activities that may be
activity. Analysis of primary and immortal- unattainable to an individual bacterium acting

www.annualreviews.org • Cell-to-Cell Communication in Bacteria 335

 ANRV255-CB21-14 ARI 1 September 2005 13:7

alone. For example, the benefit derived from can be dispersed to new environments (Dao
secretion of antibiotics or proteases may only et al. 2000, Strassmann et al. 2000). Spore
occur when these exoproducts exceed a partic- development requires a large percentage of
ular extracellular concentration, and achiev- the population to undergo a lethal differen-
ing this concentration is only possible through tiation event that leads to structures whose
the synchronous activity of a group of cells. function is to promote spore generation and
The idea that bacteria cooperate has led to dispersal. Chemical communication is re-
new questions regarding the evolution of cell- quired for these developmental events in both
cell communication in bacteria, the cost bac- D. discoidium and M. xanthus: cAMP and
teria pay for communicating, how fidelity is Differentiation-Inducing Factor initiates de-
maintained in quorum-sensing systems, how velopment of fruiting bodies in D. discoidium
cheating is controlled, and if and how “eaves- (Konijn et al. 1969, Town & Stanford 1979,
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

dropping” occurs. Town et al. 1976), whereas quorum-sensing

Although these evolutionary questions are communication controls the process in M.
new in the context of the molecular mecha- xanthus (Shimkets 1999).
nisms underlying quorum-sensing-controlled Two examples exist to date that illustrate a
behaviors, there exists an extensive litera- selection for maintenance of quorum sensing.
ture dealing with these topics in other so- In V. fischeri, mutants incapable of luciferase
by CAPES on 06/06/08. For personal use only.

cial organisms (Bourke 2001, Bradley 1999, production are outcompeted by the wild-type
Korb & Heinze 2004). For example, some bacteria in the squid host. This indicates that
social insects (e.g., ants and bees) have ster- the squid may possess a policing mechanism
ile worker castes that promote colony fitness to eliminate cheater cells. Interestingly, the
even though the workers have no chance at defect in these mutants was in luciferase it-
reproduction (Queller & Strassmann 2002). self, which suggests that the squid somehow
The predominant explanation for these be- distinguishes between cells that can and can-
haviors rests on Hamilton’s kin-selection the- not contribute to light production (Visick
ory that predicts that even without directly et al. 2000). A. tumefaciens–induced plant tu-
contributing to reproduction, organisms be- mors contain a large percentage of plasmid-
longing to a multimember group promote the free bacterial cells (Belanger et al. 1995).
inheritance of their own genes by increasing These cells have a faster growth rate and may
the fitness of closely related kin (Hamilton therefore more efficiently grow on the opine
1964a,b). A key component of kin selection nutrients produced in the plant tumors. How-
is the ability to recognize another individ- ever, plasmid-free bacteria are unable to ini-
ual as kin. The ability to distinguish between tiate new tumor formation. Interestingly, as
and communicate with specific chemical sig- bacterial density increases and nutrients be-
nal molecules may enable a type of “kin selec- come limiting, increased bacterial-bacterial
tion” in bacteria. Consistent with this, many conjugation occurs and the TI plasmid
higher social organisms rely heavily on chem- is replicated to a higher copy number. Both
ical signaling to maintain the integrity of the of these events require quorum sensing and
social order (Breed et al. 2004, Holldobler ensure that most of the bacteria acquire
1995, Queller & Strassmann 2002). copies of the plasmid before they dissemi-
Cases of sacrifice of the individual for nate to a new location. This elegant strat-
the group benefit also exist in microorgan- egy optimizes growth inside the tumor while
isms. For example, both the soil-dwelling maintaining the population’s virulence and at
bacterium Myxococcus xanthus and the slime least partially explains why quorum sensing is
mold Dictyostelium discoidium, in the absence maintained.
of nutrients, produce resistant spores that Mechanisms for eavesdropping appar-
survive nonvegetatively for long periods and ently also exist in quorum-sensing systems.

336 Waters · Bassler

 ANRV255-CB21-14 ARI 1 September 2005 13:7

P. aeruginosa does not have luxS and therefore not been defined (Rather et al. 1999). AarA has
does not produce AI-2. However, P. aerug- homology to the Drosophila melanogaster RHO
inosa detects AI-2 produced by the indige- (Gallio et al. 2002), which is a serine protease
RHO: rhomboid
nous nonpathogenic microflora present in CF required for intramembrane cleavage, release, protein
sputum samples (Duan et al. 2003). In the and activation of Epidermal Growth Factor
CF lung, P. aeruginosa exists in a complex receptor ligands (Klambt 2000, 2002). RHO
microbial community composed of a variety is essential for many developmental processes
of pathogenic and nonpathogenic bacteria. in D. melanogaster, including proper wing vein
The detection of AI-2 may alert P. aerugi- development and organization of the fly eye
nosa that P. aeruginosa is in the lung and that (Schweitzer & Shilo 1997). Consistent with
a program of gene expression that enhances the idea that AarA and RHO have a com-
persistence/virulence in the host is required. mon signaling function, expression of P. stu-
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

Consistent with this idea, CF sputum con- artii aarA in a D. melanogaster rho mutant
tains high concentrations of AI-2 and AI-2 rescued wing vein development. Likewise,
induces P. aeruginosa virulence factor expres- expression of rho in a P. stuartii aarA mutant
sion (Duan et al. 2003). In another exam- complemented the quorum-sensing signaling
ple, Salmonella enterica, which has a V. fischeri– defect (Gallio et al. 2002). Homologues of
type LuxR-type protein (SdiA) but no LuxI- RHO/AarA are nearly ubiquitous in all three
by CAPES on 06/06/08. For personal use only.

type enzyme, intercepts AHLs produced by kingdoms of life: bacteria, archea, and eu-
other LuxI-containing gram-negative bacte- karyotes (Koonin et al. 2003). Five of eight
ria. In response to these signals, S. enterica ex- tested bacterial Aar/RHO orthologues specif-
presses the rck operon and other genes that ically cleaved RHO substrates, which sug-
protect S. enterica from host defenses in the gests a widespread conservation of the mech-
intestine (Ahmer et al. 1998). This result is anism of RHO with its bacterial homologues
interpreted to mean that the AHL signals sig- (Urban et al. 2002). These fascinating re-
nify that S. enterica is in a dense population sults show that bacteria and higher eukary-
of bacteria, which can presumably be attained otes share a common cell-cell communication
only inside a host. system; however, it has not been determined
The ecological and evolutionary impli- if any cross-kingdom communication can be
cations of quorum sensing in bacteria are mediated by RHO or its homologues.
only beginning to be addressed (Travisano & A recent bioinformatics study suggests
Velicer 2004). However, continued study of that the RHO/AarA finding is not an
such questions hopefully will provide insight anomaly but rather that many signaling
into the evolution and maintenance of group mechanisms may be shared by prokaryotes
dynamics and behavior. and eukaryotes. Enzymes involved in the
production of cell-cell signaling molecules in
vertebrates have homologues in bacteria
RHOMBOID: A SHARED but are absent from plants and archea (Iyer
PROKARYOTIC AND et al. 2004). A few of numerous examples
EUKARYOTIC CHEMICAL are the enzymes phenylethanolamine N-
COMMUNICATION methyltransferase (which catalyzes the con-
MECHANISM version of norepinephrine to epinephrine),
New data suggest that some bacterial and eu- histidine decarboxylase (which catalyzes
karyotic signaling mechanisms have a com- histidine to histamine), and glutamate de-
mon evolutionary origin. The inner mem- carboxylase (which catalyzes glutamate to
brane protein AarA of Providencia stuartii is γ -aminobutyric acid). It is hypothesized that
required for the release of an extracellular eukaryotes acquired these genes from bacteria
quorum-sensing signal whose structure has through a series of horizontal gene transfer

www.annualreviews.org • Cell-to-Cell Communication in Bacteria 337

 ANRV255-CB21-14 ARI 1 September 2005 13:7

events (Iyer et al. 2004). These findings either genus-specific or promote intergenera
suggest that bacteria and eukaryotes share communication. Further, hints that interking-
enzymes responsible for many cell-cell sig- dom communication occurs are becoming in-
naling pathways. This points to the exciting creasingly prevalent. Coincident with these
possibility that prokaryotic-to-eukaryotic findings are the beginnings of an understand-
cross-kingdom communication may be more ing that prokaryotic and eukaryotic mecha-
prevalent than is currently appreciated. nisms that enhance and interfere with bac-
terial chemical communication also exist in
nature. Bacterial quorum-sensing signal de-
CONCLUSIONS tection and relay apparatuses are complex and
It is now clear that cell-cell communication is often consist of multiple circuits organized
the norm in the bacterial world and that un- in a variety of configurations. Because bacte-
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

derstanding this process is fundamental to all ria routinely exist in fluctuating environments
of microbiology, including industrial and clin- containing complex mixtures of chemicals,
ical microbiology. Our knowledge of quorum some of which are signals and some of which
sensing may ultimately affect our understand- presumably do not convey meaningful infor-
ing of higher-organism development. Quo- mation, we hypothesize that each quorum-
rum sensing was, until recently, considered to sensing network organization evolved to solve
by CAPES on 06/06/08. For personal use only.

promote exclusively intraspecies communica- the particular set of communication needs a

tion and thus enable clonal populations of bac- particular species of bacteria encounters. Ele-
teria to count their cell numbers and alter gene ments of these elegant solutions for decipher-
expression in unison. While some autoinduc- ing complex chemical vocabularies appear to
ers indeed appear to be extremely species- be conserved and used for analogous purposes
specific, new research shows that others are in eukaryotes.

ACKNOWLEDGMENTS
This work was supported by NSF grant MCB-0343821, NIH grants 5R01 GM065859
and 1R01 AI054442, ONR grant N00014-03-0183, and an NIH Postdoctoral Fellowship
(C.M.W.). We are grateful to the members of the Bassler lab for insightful discussions. We
thank Dr. D. Morrison for Figure 7 and Dr. S. Miller for Figure 8.

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Contents ARI 9 September 2005 15:36

Annual Review of
Cell and
Developmental
Biology Contents
Volume 21, 2005

Frontispiece
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David D. Sabatini p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p xiv

In Awe of Subcellular Complexity: 50 Years of Trespassing Boundaries
Within the Cell
David D. Sabatini p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
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Mechanisms of Apoptosis Through Structural Biology

Nieng Yan and Yigong Shi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p35
Regulation of Protein Activities by Phosphoinositide Phosphates
Verena Niggli p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p57
Principles of Lysosomal Membrane Digestion: Stimulation of
Sphingolipid Degradation by Sphingolipid Activator Proteins and
Anionic Lysosomal Lipids
Thomas Kolter and Konrad Sandhoff p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p81
Cajal Bodies: A Long History of Discovery
Mario Cioce and Angus I. Lamond p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 105
Assembly of Variant Histones into Chromatin
Steven Henikoff and Kami Ahmad p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 133
Planar Cell Polarization: An Emerging Model Points in the
Right Direction
Thomas J. Klein and Marek Mlodzik p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 155
Molecular Mechanisms of Steroid Hormone Signaling in Plants
Grégory Vert, Jennifer L. Nemhauser, Niko Geldner, Fangxin Hong,
and Joanne Chory p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 177
Anisotropic Expansion of the Plant Cell Wall
Tobias I. Baskin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 203
RNA Transport and Local Control of Translation
Stefan Kindler, Huidong Wang, Dietmar Richter, and Henri Tiedge p p p p p p p p p p p p p p p p p p p p 223

vi
Contents ARI 9 September 2005 15:36

Rho GTPases: Biochemistry and Biology

Aron B. Jaffe and Alan Hall p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 247
Spatial Control of Cell Expansion by the Plant Cytoskeleton
Laurie G. Smith and David G. Oppenheimer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 271
RNA Silencing Systems and Their Relevance to Plant Development
Frederick Meins, Jr., Azeddine Si-Ammour, and Todd Blevins p p p p p p p p p p p p p p p p p p p p p p p p p p p 297
Quorum Sensing: Cell-to-Cell Communication in Bacteria
Christopher M. Waters and Bonnie L. Bassler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 319
Pushing the Envelope: Structure, Function, and Dynamics of the
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Nuclear Periphery
Martin W. Hetzer, Tobias C. Walther, and Iain W. Mattaj p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 347
Integrin Structure, Allostery, and Bidirectional Signaling
M.A. Arnaout, B. Mahalingam, and J.-P. Xiong p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 381
Centrosomes in Cellular Regulation
Stephen Doxsey, Dannel McCollum, and William Theurkauf p p p p p p p p p p p p p p p p p p p p p p p p p p p 411
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Endoplasmic Reticulum–Associated Degradation

Karin Römisch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 435
The Lymphatic Vasculature: Recent Progress and Paradigms
Guillermo Oliver and Kari Alitalo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 457
Regulation of Root Apical Meristem Development
Keni Jiang and Lewis J. Feldman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 485
Phagocytosis: At the Crossroads of Innate and Adaptive Immunity
Isabelle Jutras and Michel Desjardins p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511
Protein Translocation by the Sec61/SecY Channel
Andrew R. Osborne, Tom A. Rapoport, and Bert van den Berg p p p p p p p p p p p p p p p p p p p p p p p p p p p 529
Retinotectal Mapping: New Insights from Molecular Genetics
Greg Lemke and Michaël Reber p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 551
In Vivo Imaging of Lymphocyte Trafficking
Cornelia Halin, J. Rodrigo Mora, Cenk Sumen, and Ulrich H. von Andrian p p p p p p p p p p 581
Stem Cell Niche: Structure and Function
Linheng Li and Ting Xie p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 605
Docosahexaenoic Acid, Fatty Acid–Interacting Proteins, and Neuronal
Function: Breastmilk and Fish Are Good for You
Joseph R. Marszalek and Harvey F. Lodish p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 633
Specificity and Versatility in TGF-β Signaling Through Smads
Xin-Hua Feng and Rik Derynck p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 659

Contents vii
Contents ARI 9 September 2005 15:36

The Great Escape: When Cancer Cells Hijack the Genes for
Chemotaxis and Motility
John Condeelis, Robert H. Singer, and Jeffrey E. Segall p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 695

INDEXES

Subject Index p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 719

Cumulative Index of Contributing Authors, Volumes 17–21 p p p p p p p p p p p p p p p p p p p p p p p p p p p 759
Cumulative Index of Chapter Titles, Volumes 17–21 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 762
Annu. Rev. Cell Dev. Biol. 2005.21:319-346. Downloaded from arjournals.annualreviews.org

ERRATA

An online log of corrections to Annual Review of Cell and Developmental Biology

chapters may be found at http://cellbio.annualreviews.org/errata.shtml
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viii Contents