Unité des Interactions Bactéries-Cellules, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris cedex 15, France
* Author for correspondence (e-mail: pcossart{at}pasteur.fr)
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Summary |
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Key words: HGF, Met, gC1q-R, PI 3-kinase, Cytoskeleton, Phagocytosis
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Introduction |
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Listeria monocytogenes, a Gram-positive bacterium responsible for
serious infections in immunocompromised people and pregnant women, promotes
its own internalization into various cell types by the zipper mechanism
(Cossart and Bierne, 2001;
Vazquez-Boland et al., 2001
;
Cossart, 2002
). A genetic
screen for Listeria mutants unable to enter mammalian cells led to
the discovery of two related leucine-rich repeat (LRR)-containing proteins
involved in that process: InlA (also called internalin) and InlB
(Gaillard et al., 1991
;
Dramsi et al., 1995
). Both
proteins induce particle uptake when coated on latex beads, which suggests
that they are sufficient for internalization
(Lecuit et al., 1997
;
Braun et al., 1998
).
InlA-mediated entry is restricted to a few epithelial cells, whereas InlB
promotes entry into various cell types, such as hepatocytes, epithelial cells
and endothelial cells (Dramsi et al.,
1995
; Greiffenberg et al.,
1998
; Lingnau et al.,
1995
; Parida et al.,
1998
). This tropism is determined by specific host cell receptors.
InlA is a ligand for E-cadherin, a cell adhesion molecule present in
epithelial tissues and involved in the formation of intercellular junctions
(Mengaud et al., 1996
). InlB
is an agonist of the hepatocyte growth factor receptor (HGF-R/Met), a widely
expressed receptor tyrosine kinase involved in complex cellular processes,
such as cell proliferation, dissociation, migration and differentiation
(Shen et al., 2000
). InlB
also interacts with gC1q-R, a ubiquitous glycoprotein
(Braun et al., 2000
), and with
proteoglycans (Jonquieres et al.,
2001
) that might potentiate interactions with Met.
Our knowledge of InlA- and InlB-mediated entry pathways has recently
improved. Studies of InlA point to an essential role of this protein in the
crossing of the human intestinal barrier
(Lecuit et al., 1999;
Lecuit et al., 2001
). At the
cellular level, our knowledge of the signals transduced downstream of the
InlA-E-cadherin interaction is still fragmentary
(Lecuit et al., 2000
). By
contrast, signaling pathways activated by InlB have been dissected in more
detail, revealing the strikingly potent signaling properties of InlB.
Phagocytosis and signaling via Fc receptors in macrophages share many
characteristic features with those of growth factor receptors activation
(Castellano et al., 2001;
Cox and Greenberg, 2001
).
Here, we highlight how InlB, the first-identified bacterial agonist of a
receptor tyrosine kinase, bridges these two biological processes, bringing
them closer than ever. InlB thus might prove as instrumental as ActA, IcsA and
other bacterial factors (Finlay and
Cossart, 1997
; Cossart,
2000
; Stebbins and Galan,
2001
) in addressing key issues in cell biology.
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A modular protein with two functional domains |
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The LRRs-IR `internalin' domain
InlB is a member of the internalin-related protein family, which contains
24 members in L. monocytogenes
(Glaser et al., 2001),
including the other invasion protein InlA. Most internalin-like proteins have
a short N-terminal conserved cap region, followed by several leucine-rich
tandem 22-residue repeats (LRR) and an inter-repeat (IR) region
(Dramsi et al., 1997
;
Schubert et al., 2001
). In
some cases, a second repeat region of up to three repeats of
70 residues,
the B-repeats, is present. InlB possesses eight LRRs and one B repeat.
Although all of this domain is necessary for efficient internalization by
InlB, the N-terminal 213-residue region (the cap and LRR) is sufficient to
induce entry of bacteria or InlB-coated beads into cells and to activate
signal transduction pathways (Braun et
al., 1999
; Shen et al.,
2000
).
The crystal structure of this domain reveals that it is a long and slightly
curved tube made of successive ß loop-310helix-loop motifs
(Fig. 1B)
(Marino et al., 1999;
Marino et al., 2000
). This
structure shares similarities with those of previously described
LRR-containing proteins, such as the porcine and human ribonuclease inhibitors
(Kobe and Deisenhofer, 1993
;
Papageorgiou et al., 1997
)
and the U2LRR fragment of the U2 snRNP
(Price et al., 1998
).
Recently, the structure of the whole cap-LRR-IR domain was also solved,
confirming the curved and elongated shape of the LRR region but also revealing
some interesting properties of the cap and IR regions
(Schubert et al., 2001
). The
cap region is a truncated EF-hand-like domain, comparable to one of the tandem
EF-hand calcium-binding domains identified in calmodulin and related proteins
(Babu et al., 1988
;
Flaherty et al., 1993
).
However, the presence of potential calcium-binding sites in this region is
controversial (Marino et al.,
1999
; Schubert et al.,
2001
). The IR region is structurally related to the immunoglobulin
(Ig)-like domain, several copies of which are present in antibodies and
numerous eukaryotic cell-surface proteins
(Harpaz and Chothia, 1994
). It
is not yet known whether this Ig-like domain makes specific contacts with
eukaryotic cell-surface proteins or whether it has only a structural role in
stabilizing the LRR region. The curvature of the internalin domain makes it
ideally shaped to embrace globular protein domains. Interestingly, LRR and
Ig-like domains in other bacterial proteins are mostly found in virulence
factors (Kajava, 1998
;
Schubert et al., 2001
). The
fusion of these two domains in InlB and in other internalins may represent an
optimal adaptation to its eukaryotic host during evolution.
The bacterial-surface-anchoring domain
The C-terminal region of InlB contains three tandem 80-residues
repeats, which are highly basic and start with the dipeptide GW
(Braun et al., 1997
). These
repeats mediate a loose association of the protein with the bacterial surface,
mainly through non-covalent interactions with lipoteichoic acid, a
membrane-anchored polymer present on the surface of Gram-positive bacteria
(Jonquieres et al., 1999
).
Strikingly, they also confer on InlB the unusual property of adhering to
bacteria when added from the extracellular medium. Association/re-association
of InlB with bacteria after secretion or release from the bacterial surface
might play an important role during invasion of cells. Indeed, InlB is buried
in the bacterial cell wall, and this puzzling localization suggested that
external factors regulate its accessibility, possibly by acting on GW repeats.
This hypothesis is supported by the demonstration that GW repeats bind to
cellular proteoglycans and that these interactions are required for efficient
entry (see below) (Jonquieres et al.,
2001
).
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Host cell receptors |
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Met is a disulfide-linked heterodimer composed of a 45 kDa extracellular
-subunit and a 145 kDa transmembrane ß-subunit, which contains the
tyrosine kinase catalytic domain (Furge et
al., 2000
). Receptor activation is mediated in part by
autophosphorylation of specific tyrosine residues within the intracellular
region. Phosphorylation of two tyrosine residues (Y1234 and Y1235) within the
tyrosine kinase domain activates the intrinsic kinase activity of the
receptor, whereas the two phosphorylated tyrosine residues in the C-terminus
(Y1349 and Y1356) form a specific docking site for multiple signal transducers
and adapters. In common with the natural ligand HGF, purified InlB stimulates
the sequential tyrosine phosphorylation of Met, recruitment and
phosphorylation of Gab1, Cbl and Shc, and formation of complexes containing
these adapters and the p85 subunit of PI 3-kinase.
InlB interacts with the extracellular domain of Met through its LRR domain,
but the full-length protein is required for maximal activation
(Shen et al., 2000).
Interestingly, several pieces of evidence indicate that InlB does not strictly
mimic HGF. First, HGF and InlB do not share sequence similarity. HGF is a
disulfide-linked
ß heterodimer that shows structural similarity to
enzymes of the blood coagulation cascade
(Stella and Comoglio, 1999
).
The 69 kDa
subunit contains an N-terminal hairpin loop and four
kringle domains, and the 34 kDa ß subunit contains a catalytically
inactive serine proteinase domain (Fig.
1A). The N and first kringle domain (NK1) in the
chain are
sufficient to bind to Met, but the crystal structures of the LRR in InlB and
the NK1 in HGF seem structurally unrelated
(Chirgadze et al., 1999
).
Second, InlB and HGF do not seem to interact with Met at the same site,
because an excess of HGF does not inhibit binding of InlB to Met
(Shen et al., 2000
). Third,
InlB-induced phosphorylation of Met is more transient (peaking after 10-20
minutes and undetectable at 60 minutes) than that produced by HGF (which
remains unchanged after two hours). Whether the difference in binding-site
location explains this difference in the duration remains to be established.
Interestingly, differences in the kinetics of Met activation seem to induce
divergent biological responses triggered by this receptor
(Boccaccio et al., 2002
). In
common with HGF, InlB stimulates scattering of MDCK cells; however, whether
InlB can elicit all of the complex responses induced by HGF, such as
mitogenesis and morphogenesis, is not known. These responses might also depend
on whether Met is activated by bacterial-surface-bound InlB or by a soluble
form released in the extracellular medium.
Proteoglycans
Activation of Met by HGF is enhanced by glycosaminoglycans (GAGs), such as
heparan sulfates, which are negatively charged polysaccharides present at the
surface of all cell types (Trusolino et
al., 1998). GAGs can be secreted into the extracellular medium but
usually decorate a protein moiety in proteoglycans. Proteoglycans are required
for optimal activity of HGF and many other growth factors
(Rusnati and Presta, 1996
;
Kresse and Schonherr, 2001
;
Rubin et al., 2001
), possibly
immobilizing them at the cell surface, protecting them from degradation,
transferring them to the high-affinity receptors and facilitating their
oligomerization. Interestingly, InlB also binds to GAGs through its GW
repeats, and the presence of GAGs on the cell surface significantly increases
InlB-dependent invasion (Jonquieres et
al., 2001
). In addition, the internalin domain of InlB is less
efficient in activating Met and in inducing cell scattering than the
full-length InlB protein (Shen et al.,
2000
). Thus, binding of GW repeats to cellular GAGs could enhance
interaction of the LRR domain with Met.
Soluble heparin detaches InlB from the bacterial surface and induces InlB clustering, as it does with HGF. This suggests that GAGs compete with lipoteichoic acid for binding to GW repeats. Although GAGs and lipoteichoic acid are structurally different, they each have a highly negative charge density, whereas GW repeats are highly basic. GAGs might therefore stimulate the release of InlB as a soluble factor, which could act as a growth factor independently of invasion. As in the case of HGF, cellular responses to InlB might depend on the GAG composition of the target cell surface.
gC1q-R
InlB interacts with another cellular protein, gC1q-R, identified through
affinity chromatography (Braun et al.,
2000). gC1q-R is a highly acidic multiligand-binding glycoprotein
of 33 kDa that is predominantly associated with the mitochondria and the
nucleus but also found at the cell surface and in body fluids. Originally
identified as the receptor for the globular head of C1q, the first component
of the complement cascade, gC1q-R is in fact a multifunctional protein that
has affinity for diverse ligands, including plasma, cellular and microbial
proteins (Ghebrehiwet et al.,
2001
). It interacts with several viral proteins, such as HIV-1 Rev
and Tat (Luo et al., 1994
),
protein V of adenovirus (Matthews and
Russell, 1998
), Epstein-Barr virus nuclear antigen-1 (EBNA-1)
(Wang et al., 1997
) and
hepatite C virus core protein (Kittlesen
et al., 2000
), and at least two bacterial proteins, InlB and
protein A from Staphylococcus aureus
(Nguyen et al., 2000
). This
molecule could thus be involved in several aspects of host-pathogen
interactions, although its physiological roles are not yet clear.
The crystal structure of human gC1q-R reveals a donut-shaped ternary
complex (Jiang et al., 1999)
but provides little clues to its mode of attachment at the cellular surface.
It is not a GPI-anchored protein; instead it could bind to the cell surface by
ionic interactions. Nevertheless, interaction of InlB with a
surface-associated gC1q-R form appears to be critical for InlB-mediated entry,
since gC1q-R antibodies and C1q compete with InlB for binding to gC1q-R and
are able to inhibit specifically InlB-dependent entry of L.
monocytogenes into cells (Braun et
al., 2000
). However, antibodies against gC1q-R only partially
inhibit InlB-mediated signaling. Therefore, an attractive hypothesis is that
gC1q-R facilitates interaction of InlB with Met. This bridging effect could be
cell-type dependent, relying on the presence of surface-bound gC1q-R.
Interestingly recent data indicate that the highly acidic protein gC1q-R binds
to the basic GW repeats of InlB (M. Marino, M. Banerjkee, T. Chapman et al.,
unpublished). Therefore, it may modulate InlB accessibility in a similar way
to proteoglycans. Another intriguing question is whether gC1q-R interacts with
InlB intracellularly, after the escape of bacteria from the phagocytic
vacuole. Further studies are therefore required to clarify the role of gC1q-R
in the cellular infectious process.
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InlB-mediated internalization |
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Actin rearrangements
Since InlB-Met signaling leads to both phagocytosis
(Fig. 2A) and membrane ruffling
(Fig. 2B), these two types of
actin-based process might share some downstream effectors. Both require actin
polymerization, tyrosine phosphorylation and PI 3-kinase activation
(Ireton et al., 1996;
Braun et al., 1998
;
Ireton et al., 1999
), as does
FcR-mediated phagocytosis (Cox and
Greenberg, 2001
). Recently, the Arp2/3 complex, cofilin,
LIM-kinase and the GTPase Rac, all well known regulators of transient actin
polymerization/depolymerization, were shown to be involved in InlB-mediated
actin reorganization (Bierne et al.,
2001
). The Arp2/3 complex is an assembly of seven proteins that
together promote nucleation of actin filaments on the side of older filaments
and therefore participate in the formation of branched actin networks
(Machesky and Gould, 1999
;
Welch, 1999
;
Robinson, 2001
). It is
recruited to InlB-induced phagocytic cups and membrane ruffles. Moreover,
formation of these actin-based structures is inhibited when Arp2/3 is
sequestered by the C-terminus of Scar
(Bierne et al., 2001
). These
results suggest that the Arp2/3 complex regulates actin dynamics during
InlB-induced phagocytosis, as it does during FcR and CR3-mediated phagocytosis
(May et al., 2000
) and at the
leading edge of motile mammalian cells
(Bailly et al., 1999
;
Svitkina and Borisy,
1999
).
Actin polymerization is thought to provide the driving force that propels
membranes around the bacterium. However, the shaping of the phagocytic cup
also requires actin depolymerization events, particularly beneath the
particle, to facilitate retraction of the cup. Proteins of the ADF/cofilin
family (Bamburg, 1999;
Chen et al., 2000
), which
increase actin depolymerization at free pointed ends are candidates for
mediators of this process, although they have been characterized mainly as
enhancers of actin dynamics rather than actin disrupters. These proteins
increase the rate of actin turnover and the number of free actin ends
available for polymerization (Carlier et
al., 1997
; Rosenblatt et al.,
1997
; Chan et al.,
2000
). They are inactivated through LIM-kinase-induced
phosphorylation (Arber et al.,
1998
; Yang et al.,
1998
) and reactivated through dephosphorylation.
Interestingly, analysis of the role of cofilin during InlB-induced
phagocytosis has shown that InlB participates in both formation and disruption
of the actin phagocytic cup (Bierne et
al., 2001). First, not only is cofilin recruited at InlB-induced
F-actin cups, but, strikingly, it seems to accumulate progressively and
transiently around the phagosome (Fig.
3,1). Second, InlB-induced phagocytosis is inhibited in cells
deregulated for the cofilin phosphocycle. Inactivating cofilin by LIM-kinase
induces F-actin overaccumulation at the entry site of InlB particles and
inhibits closure of the phagocytic cup
(Fig. 3,3). Conversely,
increasing cofilin activity by overexpressing a constitutively active cofilin
mutant (S3A (cofilin), or a dominant-negative LIMK1 mutant, induces loss of
F-actin at phagocytic cups and also inhibits phagocytosis
(Bierne et al., 2001
)
(Fig. 3,2). Together, these
data fit with a two-step model (Fig.
3). At low activity, controlled by LIM-kinase, cofilin could be
involved in the phagocytic cup extension by stimulating actin dynamics. Then,
dephosphorylation of cofilin and its progressive accumulation on filaments
would ultimately favor the disassembly of the actin network during the
retraction of the phagocytic cup and around the newly formed phagosome. It
will now be important to address the role of Slingshot (SSH), the newly
identified cofilin phosphatase (Niwa et
al., 2002
) in this process.
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From Met to the cytoskeleton
What links Met activation and recruitment of Arp2/3, cofilin and
LIM-kinase? Likely candidates are the Rho-GTPases Rac and Cdc42, which
regulate actin cytoskeleton rearrangements both during lamellipodia formation
and phagocytosis (Cox et al.,
1997; Caron and Hall,
1998
; Ridley,
2001
). Indeed, HGF activates Cdc42, Rac and PAK
(Royal et al., 2000
), which
is an upstream activator of LIM-kinase
(Edwards et al., 1999
).
Recruitment of Rac to the Met receptor seems to require the adapters CrkII and
Dock180 (Furge et al., 2000
).
It is still unknown whether Rac and Cdc42 are activated by
guanine-nucleotide-exchange factors (GEFs) downstream of Met. InlB-induced
membrane ruffling in Vero cells is impaired by Rac1-N17 and Cdc42-N17
dominant-negative mutants, which suggests that both Rac and Cdc42 are involved
in InlB-mediated cytoskeletal rearrangements. However, only Rac1-N17 blocks
InlB-induced phagocytosis in Vero cells, whereas Cdc42-N17 has no effect on
entry in this cell line (Bierne et al.,
2001
). This observation suggests that the formation of the F-actin
cup is controlled mainly by Rac in this system. InlB-Met interactions probably
elicit a Rac/PAK/LIM-kinase/cofilin cascade. In addition, Rac has recently
been shown in other systems to activate the Arp2/3 complex by a cascade of
events involving the adapters IRSp53 and WAVE, a member of the Wiskott-Aldrich
Syndrome protein (WASP) family (Miki et
al., 2000
). The current model is that activated Rac recruits
IRSP53, which binds to the proline-rich region of WAVE. As a result, the
C-terminal region of WAVE is exposed and activates the Arp2/3 complex
(Takenawa and Miki, 2001
).
Preliminary results indicate that these molecules play a role in
InlB-Met-induced cytoskeletal rearrangements (H.B. and P.C., unpublished).
Putative roles for PI 3-kinase
PI 3-kinase is an essential component of InlB-mediated phagocytic
signaling, but its downstream effectors are not yet identified. In
FcR-mediated phagocytosis, PI 3-kinase appears to function in pseudopod
extension and closure of the phagocytic cup by regulating exocytosis of
endomembranes and membrane fusion events
(Araki et al., 1996;
Booth et al., 2001
;
Cox and Greenberg, 2001
).
Inhibition of PI 3-kinase does not prevent accumulation of the subcortical
actin at the sites of particle attachment, which suggests that it does not
regulate actin polymerization. However, reorganization of the cortical actin
cytoskeleton required for lamellipodia and membrane ruffle formation in
response to various stimuli (Wymann and
Arcaro, 1994
; Kotani et al.,
1994
; Reif et al.,
1996
; Arrieumerlou et al.,
1998
; Hill et al.,
2000
), including soluble InlB
(Ireton et al., 1999
), does
require PI 3-kinase activity, highlighting a direct connection between PI
3-kinase activation and the cytoskeleton in InlB-Met signaling. To reconcile
these findings, we propose that PI 3-kinase plays multiple roles in
InlB-mediated internalization, including recruitment of both membrane vesicles
and actin regulatory proteins. Proteins of the Vav family
(Bustelo, 2001
), which act as
GEFs for Rac and are downstream effectors of PI 3-kinase signalling
(Han et al., 1998
), are
involved in both growth factor and phagocytic signalling
(Moores et al., 2000
;
Patel et al., 2002
). They
might have a role in Rac activation downstream of Met. One possible scenario
is that Met clustering recruits and activates Rac, leading to the initiation
of actin polymerization. Then, PI 3-kinase activity leads to a Vav-induced
sustained activation of Rac, which drives actin rearrangements at the
phagocytic cup. In line with this idea, although recruitment of activated Rac
at the plasma membrane is sufficient to trigger phagocytosis, it is not
sufficient to promote a detectable accumulation of F-actin at the phagocytic
cup (Castellano et al.,
2000
).
New effectors
A powerful way of identifying new components of the phagocytic machinery is
to isolate phagocytic vacuoles and proceed to a proteomic approach
(Duclos and Desjardins, 2000;
Garin et al., 2001
). In recent
work, analysis of vacuoles produced during the uptake of InlB-coated beads
identified MSF as a putative new effector of the InlB-dependent pathway
(Pizarro-Cerda et al., 2002
).
MSF is not only present in phagosomes but also recruited to the entry site of
InlB-coated beads, where it colocalizes with actin. It is a member of the
septin family of GTPases (Osaka et al.,
1999
), which form filaments that can interact with actin-based
structures (Field et al.,
1996
; Kinoshita et al.,
1997
). Septins regulate vesicle transport in exocytosis through
interaction with SNARE proteins (Beites et
al., 1999
). However, the precise function of MSF in bacterial
uptake is unknown.
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Other InlB-mediated cellular responses |
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PLC-1 and calcium
Phospholipases C play critical roles in receptor-mediated signal
transduction via the generation of inositol 1,4,5-trisphosphate
[InsPtd(1,4,5)P3] and diacylglycerol (DAG) after
hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns
(4,5)P2]. InsPtd(1,4,5)P3 induces
calcium release from internal stores, and DAG activates a large family of
calcium/phospholipid-dependent protein kinase C (PKC) isoenzymes. The
PLC-1 isoform is widely expressed and activated by a variety of
receptor and non-receptor tyrosine kinases by tyrosine phosphorylation
(Carpenter and Ji, 1999
). In
addition, the activity of PLC-
1 is enhanced through binding of the PH
and SH2 domains of the enzyme to the PI 3-kinase product
PtdIns(3,4,5)P3
(Falasca et al., 1998
;
Rameh et al., 1998
).
InlB activates PLC-1 in HEp-2 cells and induces intracellular
calcium rises (Bierne et al.,
2000
). Activation of PLC-
1 results from its PI 3-kinase
dependent association with tyrosine-phosphorylated proteins but does not
require tyrosine phosphorylation of PLC-
1. It is possible that the
adapter Gab1, which becomes tyrosine phosphorylated in response to InlB
stimulation, recruits PLC-
1 as it does in HGF-Met signaling
(Gual et al., 2000
). InlB
stimulation induces very transient increases in intracellular
InsPtd(1,4,5)P3 and calcium levels and does not provoke a
sustained response. Therefore the intracellular Ca2+ released is
likely to activate highly localized cellular processes, which would be able to
respond to slight changes in the concentration of this potent signaling ion
(Bootman et al., 2001
).
What then is the function of PLC-1 in InlB-mediated signaling?
PLC-
has been proposed to be involved in actin rearrangements, because
PtdIns(4,5)P2 and calcium are well known regulators of
actin-binding proteins (Lee and Rhee,
1995
). However, PLC-
1 is not required for the
reorganization of the actin cytoskeleton that occurs during InlB-induced
phagocytosis (Bierne et al.,
2000
). Indeed, entry of InlB-coated beads or InlB-expressing
bacteria is not affected by the PLC inhibitor U73122 or the calcium chelator
BAPTA/AM. In addition, L. monocytogenes internalization is not
decreased in Plcg1-knockout cells. Therefore, InlB-mediated
PLC-
1 activation and intracellular calcium rises are apparently not
involved in the internalization process. Similarly, the PLC-
/calcium
signaling cascade that occurs upon ingestion of particles by professional
phagocytes is not a prerequisite for uptake
(Di Virgilio et al., 1988
).
Interestingly, recruitment of PLC-
1 is not required for HGF-mediated
cell scattering, and the inhibitor U73122 does not block this process, which
suggests that PLC-
signaling is also not involved in HGF-mediated
cytoskeletal reorganization. By contrast, PLC-
appears to be critical
for HGF-mediated tubular morphogenesis, a phenomenon similar to
differentiation (Machide et al.,
1998
). PLC-
1 also mediates an intracellular signal for the
HGF-enhanced mitogenesis in rat primary hepatocytes
(Okano et al., 1993
). Taken
together, these data suggest that InlB-induced PLC-
1 activation and
calcium mobilization are probably involved in post-internalization steps, such
as the control of cell growth and/or of gene expression.
Akt and NF-B
The eukaryotic transcription factor NF-B is an important regulator
of many genes involved in inflammation, immunity, stress responses and the
inhibition of apoptosis. In unstimulated cells, NF-
B is sequestered in
the cytoplasm by the inhibitory protein I
B
(May and Ghosh, 1997
;
Baeuerle, 1998
;
May and Ghosh, 1999
).
Signal-induced phosphorylation and consequent proteolytic degradation of
I
B allows NF-
B to enter the nucleus and induce transcription.
Several bacterial surface components, such as lipopolysaccaride (LPS) in
Gramnegative bacteria and lipoteichoic acids (LTA) in Grampositive bacteria,
are potent activators of NF-
B. InlB also activates NF-
B in some
macrophages and epithelial cell lines and induces NF-
B-dependent
expression of the cytokines TNF-
and IL6
(Mansell et al., 2000
). The
effect is rapid and sustained and involves the degradation of both
I
B
and I
Bß.
Mansell et al. have recently examined the InlB-NF-B signaling
cascade in murine J774 macrophages
(Mansell et al., 2001
), in
which Met is expressed (N. Khelef and P.C., unpublished). First, in common
with HGF, InlB induces the sequential activation of the small G-protein Ras
and of PI 3-kinase. Then, PI 3-kinase activates the Akt/protein kinase B
(PKB), which activates NF-
B by an uncharacterized pathway. Several
other studies indicate that Akt is involved in NF-
B activation
(Kane et al., 1999
;
Ozes et al., 1999
;
Burow et al., 2000
). One
proposed mechanism is that Akt activates the I
B kinase complex (IKK)
that phosphorylates I
B.
Interestingly, Akt is thought to play an important role in protecting cells
from apoptosis and in promoting cell survival
(Downward, 1998;
Burow et al., 2000
). In
particular, it was recently shown to be part of anti-apoptotic HGF and PDGF
signaling (Romashkova and Makarov,
1999
; Xiao et al.,
2001
). Therefore, one attractive hypothesis is that InlB-mediated
Akt activation plays a role in the survival of the infected host cell. Since
L. monocytogenes is an intracellular pathogen, host cell survival
could facilitate the dissemination of the bacteria in tissues. The role of
NF-
B activation upon InlB stimulation may not be linked to
anti-apoptosis, since it has been recently shown that HGF-induced NF-
B
activation is dispensable for the anti-apoptotic function of HGF
(Muller et al., 2002
).
Further studies are require to understand the precise role of this regulator
in the InlB pathway.
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Concluding remarks |
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InlB acts as an invasin in vitro and promotes entry into cells that are not
(or poorly) permissive for the other invasion protein InlA entry pathway, such
as hepatocytes (Dramsi et al.,
1995) and endothelial cells
(Greiffenberg et al., 1998
;
Parida et al., 1998
). Is InlB
really an invasin in vivo? In the murine model, a
inlB mutant
of L. monocytogenes produces fewer bacterial counts in the liver
(Dramsi et al., 1995
;
Gaillard et al., 1996
).
However, it is not yet clear whether InlB promotes invasion of hepatocytes per
se or whether another process is involved, such as intracellular bacterial
multiplication (Gregory et al.,
1997
). The role of the InlB pathway in other tissues, and its
interplay with the InlA pathway, deserves more investigation.
InlB shares properties with HGF in vitro. Does InlB act as a growth factor
in vivo? If it were the case, it would probably have to be released from the
bacterial surface as a soluble signaling molecule. This phenomenon remains to
be demonstrated. Activation of cell growth and cell survival by InlB,
especially that of hepatocytes, endothelial cells and macrophages, could be of
primary importance for bacterial dissemination in tissues. Moreover, in common
with HGF, soluble InlB triggers scattering of some epithelial cells
(Shen et al., 2000). Does
InlB open cellular junctions in epithelia and facilitate interaction between
InlA and its receptor E-cadherin, as recently proposed
(Cossart, 2001
)? Does InlB
share the deleterious effects of HGF, which plays a role in metastasis? Much
effort is still required to discover all of the properties of this fascinating
protein.
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Acknowledgments |
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References |
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