3 nod
Post on 24-May-2015
520 Views
Preview:
TRANSCRIPT
Available online at www.sciencedirect.com
Nod-like receptors: sentinels at host membranesDana J Philpott1 and Stephen E Girardin2
Innate immune detection of danger signals and microbial motifs
is achieved by distinct families of pattern recognition
molecules. These include the membrane-anchored Toll-like
receptors (TLRs), as well as cytosolic Nod-like receptors
(NLRs) and Rig-I-like receptors (RLRs). The precise mode of
NLR activation in the host cytosol remains poorly defined, as
evidence of direct interaction between NLRs and danger- or
microbial-associated molecular patterns remains elusive.
However, a number of convergent observations now suggest
that activation of some NLRs occurs at the level of host
membranes or as a consequence of membrane damage. This
review focuses on this emerging theme and discusses the
functional consequences of innate immune sensing at the
vicinity of the membrane.
Addresses1 Department of Immunology, University of Toronto, Toronto, Canada2 Department of Laboratory Medicine and Pathobiology, University of
Toronto, Toronto, Canada
Corresponding authors: Girardin, Stephen E
(stephen.girardin@utoronto.ca)
Current Opinion in Immunology 2010, 22:428–434
This review comes from a themed issue on
Host pathogens
Edited by Adolfo Garcia-Sastre and Philippe Sansonetti
Available online 3rd June 2010
0952-7915/$ – see front matter
# 2010 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coi.2010.04.010
Innate immunity relies on the detection of danger- and
microbial-associated molecular patterns (DAMPs and
MAMPs, respectively) by several families of secreted
or cellular pattern-recognition molecules (PRMs). Several
classes of cellular PRMS are directly responsible for the
induction of signal transduction pathways that shape the
innate immune response, and these include the type I
transmembrane molecules of the Toll-like receptor
(TLR) family as well as the cytosolic Nod-like receptors
(NLRs) and Rig-I-like receptors (RLRs) [1].
The NLR familyNLRs are defined by the juxtaposition of a central
(NACHT) domain and C-terminal leucine-rich repeat
(LRR) domain [2,3]. Twenty-two NLR proteins are pre-
sent in the human genome, which are further grouped
into subfamilies on the basis of their N-terminal region.
Upon activation, NLR proteins trigger a number of signal
Current Opinion in Immunology 2010, 22:428–434
transduction cascades, which include the pro-inflamma-
tory NF-kB (for Nod1 and Nod2) [2,3] and the caspase-1
inflammasome (for NLRC4, NLRP3 and NLRP1) path-
ways [4] as well as activation of autophagy (Nod1, Nod2
and NLRC4) [5,6] and cell death (including NLRC4,
NLRP1 and NLRP3) [5,7,8].
In the past few years, the identification of the nature of
the molecular patterns detected by NLRs has been the
subject of intense investigations, and the key role of
NLRs in the cytosolic detection of various MAMPs
and DAMPs is clearly emerging. Nod1 and Nod2 detect
specific structures within bacterial peptidoglycan [2], and
NLRC4 senses bacterial flagellin [9] as well as the bac-
terial type III secretion apparatus [10]. The inflamma-
some-triggering protein NLRP3 was shown to detect a
wide array of molecules, including ATP, potassium efflux,
muramyl dipeptide (MDP), bacterial toxins, xenocom-
pounds (silica, asbestos, and aluminium hydroxide), viral
nucleic acids, b-amyloid fibrils and malarial hemozoin
(reviewed in [11,12]). NLRP1 was also found to be a
pleiotropic sensor, mediating the detection of anthrax
lethal toxin, MDP, and potassium efflux. The extremely
diverse repertoire of the molecular triggers activating the
caspase-1 inflammasome led to the hypothesis that
NLRP proteins must in fact be activated by common
upstream cellular events [12–14]. The NADPH-depend-
ent generation of reactive oxygen species (ROS) or rup-
ture of the lysosomal membrane could represent such
common activators of the caspase-1 inflammasome. In
support of the former, recent evidence has shown that
NLRP3 interacts with thioredoxin-interacting proteins
(TXNIP) through the ROS-induced liberation of this
protein from thioredoxin [15].
The interest in NLR biology is also driven by the striking
association between mutations or polymorphisms in NLR
or NLR-associated genes and human inflammatory dis-
orders, which underscores the importance of this family in
the control of inflammation [16,17]. In particular, Nod2has been identified as the first susceptibility gene for
Crohn’s disease (CD) and Blau syndrome, and mutations
in Nlrp3 (also known as Cryopyrin or Cias1) are associated
with several rare autoinflammatory disorders, including
Muckle–Wells syndrome, chronic infantile neurological
cutaneous and articular syndrome (CINCA) and familial
cold urticaria (FCU), and common variants in Nlrp3 have
also been recently associated with CD [16,17]. In
addition, polymorphisms in Nod1 have been associated
with asthma and atopic eczema, and Nlrp1 was identified
as a susceptibility gene for vitiligo, Addison’s disease and
type I diabetes [16,17].
www.sciencedirect.com
Sentinels at host membranes Philpott and Girardin 429
Signal transduction cascades triggered by NLR engage-
ment have been studied in detail. A general common
mechanism of activation likely requires the (homo- or
hetero-) oligomerization of NLR proteins, resulting in the
recruitment of adaptor proteins, such as Rip2 for Nod1
and Nod2, or ASC for NLRC4, NLRP1 and NLRP3 [2,3].
Rip2 is essential for mediating Nod1- and Nod2-depend-
ent activation of NF-kB and MAPK signaling [18], but is
dispensable for the Nod-driven recruitment of the autop-
hagosome at the site of bacterial entry in murine embryo-
nic fibroblasts [6]. The exact requirement of ASC for
NLRP and NLRC4 signaling is more complex, since this
adaptor protein was found to be either essential or dis-
pensable in multiple models of NLR-dependent acti-
vation of the caspase-1 inflammasome [12].
The nature of the events occurring upstream of NLR
engagement, and in particular the exact mode of the
detection of MAMPs or DAMPs by NLRs, remains less
understood. In the vast majority of cases, direct detection
or interaction between NLRs and either MAMPs or
DAMPs has not been demonstrated. An exception to this
was a recent study in which the authors performed an invitro reconstitution of the NLRP1 inflammasome and
demonstrated oligomerization of NLRP1 and caspase-1
through addition of MDP [19], therefore suggesting the
existence of a direct interaction between NLRP1 and
MDP. In the case of NLRP3, as discussed above, it is
believed that secondary cellular events such as ROS-
induced modifications or lysosomal damage might play
a key role in activation [12–14]. The cytosolic sub-cellular
localization where NLR engagement occurs is also not
clearly established, because of the lack of sensitive tools
to probe NLR activation by microscopy techniques.
However, recent biochemical evidence points to a tight
relation between NLR activation and sub-cellular vicinity
to plasma or internal membranes. An intriguing possib-
ility would suggest that NLR localization at membranes is
not coincidental with NLR activation but actually a
prerequisite for physiological activation. The following
discussion reviews this hypothesis.
Evidence for the activation of NLRs at hostmembranesNod1 and Nod2
The first indication that NLRs function at host mem-
branes came from a study by Barnich et al. who demon-
strated that Nod2-dependent responses to MDP
correlated with the capacity of the protein to localize
to the plasma membrane [20]. Importantly, the authors
identified that the C-terminal end of the protein was
responsible for membrane targeting, therefore explaining
the defective MDP sensing capacity of the CD-associated
Nod2 variant Nod2 3020insC, which lacks the last 33
COOH-terminal amino acids of the protein. A recent
study further validated these observations by showing
that Rip2 was also found at the plasma membrane, and
www.sciencedirect.com
demonstrated that enforced targeting of Rip2 to the
plasma membrane was sufficient to trigger NF-kB [21].
Similar results were also reported for Nod1, as both Nod1
and the IKKg subunit of the IKK complex, critical for
NF-kB activation, were found enriched at the plasma
membrane, at the site of bacterial entry [22].
The consequence of targeting Nod protein to the plasma
membrane is likely complex and dynamic. Indeed, relo-
calization of Nod2 from a Triton-X-100 insoluble to
soluble fractions with cytochalasin D, or exclusion of
Nod2 from membrane ruffles, were found to correlate
with enhanced capacity to trigger NF-kB pathways [23],
suggesting that, in basal conditions, Nod-dependent
activity might be locked out by membrane- or actin-
associated cofactors. In agreement for this, two indepen-
dent studies identified the membrane-associated protein
Erbin as a Nod2-interacting protein, and demonstrated
that Erbin acted as a negative modulator of Nod2-de-
pendent pathways [24,25]. Other membrane-associated
proteins have been shown to interact with Nod proteins
and to modulate their function. The Rho GTPase Rac1,
which is essential for the regulation of membrane ruffling
and is also a component of the NADPH oxidase complex,
was found to interact with Nod2 and to negatively
regulate its function [23,26]. In contrast, the guanine
exchange factor GEF-H1, which plays important roles
in RhoA activation in the context of Shigella invasion in
non-myeloid cells, was found to interact with Nod1 and
positively modulate its function [27]. Finally, the protein
Duox2 of the NADPH oxidase complex was found to
interact with Nod2 and to potentiate its function [28].
The opposite effect of two members of the NADPH
oxidase complex (Rac1 and Duox2) on Nod2-dependent
pathway remains unclear, but might reflect the more
general impact of membrane targeting on Nod activity,
acting as a negative or positive modulator of Nod function
in resting versus ROS-generating or membrane-remodel-
ing conditions, respectively (Figures 1 and 2).
NLRP1 and NLRP3
The functional relation between the activity of NLRP3
and NLRP1 and host membranes is indirectly inferred by
the nature of the MAMPs or DAMPs that they detect.
Indeed, the fact that potassium efflux at the plasma
membrane is sufficient to trigger NLRP3 and NLRP1
activation [29,30] is a strong indication that these NLRs
are activated at the vicinity of the plasma membrane,
where the dynamic variation of [K+] is the greatest.
Similarly, NADPH oxidase-dependent ROS levels likely
diffuse poorly into the cytosolic space because of their
unstable nature and the presence of a number of buffering
cellular antioxidants. Therefore, NADPH-generated
ROS concentration must display a dynamic gradient
resulting from the flux of their generation, with the
highest concentration found at the vicinity of the plasma
or phagocytic membranes. Another interesting possibility
Current Opinion in Immunology 2010, 22:428–434
430 Host pathogens
Figure 1
Activation of Nod1 and Nod2 at host membranes. Nod proteins can detect peptidoglycan fragments produced in host phagosome or phagolysosome
during degradation of phagocytosed bacteria. The nature of the transporters involved in the translocation of peptidoglycan from the phagolysosome to
the cytosol remains unknown. Peptidoglycan fragments in the extracellular milieu can also enter cells by endocytosis. In HEK293T cells, peptidoglycan
fragments translocate to the cytosol at least in part through the oligopeptide transporter SLC15A4. Nod proteins interact with membrane-associated
proteins GEF-H1, Erbin, as well as Rac1 and Duox2 from the NADPH oxidase complex. Nod1 and Nod2 also detect invading bacteria and trigger the
recruitment of the autophagic machinery (see also Figure 3).
would be that NLRP proteins could directly detect
membrane damage or leakage. This idea is consistent
with the fact that several membrane toxins that insert into
host membranes, such as listeriolysin O, streptolysin O, a-
hemolysin or the anthrax lethal toxin were found to
trigger NLRP-dependent caspase-1 inflammasomes
[12,13]. In addition, multiple lines of evidence point to
a role of lysosomal damage and cytosolic leakage of
cathepsin B in NLRP3 activation [13], suggesting that
NLRP protein may act as intracellular sensors of host
membrane integrity.
NLRC4
NLRC4 was found to detect intracellular bacterial fla-
gellin [31,32]. While this detection could in theory occur
anywhere in the host cytosol in the case of flagellated
bacteria that escape the phagocytic vacuole, it is inter-
esting to note that NLRC4 activation by Salmonella and
Legionella requires both flagellin and functional type III or
Type IV secretion systems, which insert into host mem-
branes [31,32]. Together, these observations suggest that
the detection of flagellin by NLRC4 might be functional
in the context of membrane damage. In agreement with
Current Opinion in Immunology 2010, 22:428–434
this, NLRC4 has been recently shown to detect directly
the basal body rod component of the type III secretion
system apparatus of several Gram-negative bacteria, in-
cluding Salmonella typhimurium, Shigella flexneri and Pseu-domonas aeruginosa. It must be noted that Naip5, another
NLR protein previously identified as a critical protein
implicated in the restriction of Legionella growth in macro-
phages, was also shown to participate in intracellular
flagellin detection, together with NLRC4 [33].
NLRX1
NLRX1 localizes to mitochondria and is the only known
NLR protein that targets specifically a cellular organelle
[34,35]. Recent evidence demonstrated that NLRX1
translocates to the mitochondrial matrix via its N-terminal
addressing sequence and biochemical studies identified
that the protein associates with the mitochondrial inner
membrane, at least in part, through its interaction with
UQCRC2, a matrix-exposed core component of the com-
plex III of the respiratory chain [36]. It is possible that this
interaction contributes to the capacity of NLRX1 to
regulate mitochondrial ROS generation, as previously
demonstrated by over-expression studies. Finally, it has
www.sciencedirect.com
Sentinels at host membranes Philpott and Girardin 431
Figure 2
Activation of the inflammasome-triggering NLR proteins at host membranes. Bacterial processing in phagosome or phagolysosome generates
molecules (including peptidoglycan and flagellin) that translocate to the cytosol and trigger the caspase-1 inflammasome through NLRP3 and NLRC4/
NAIP5, respectively. NLRC4 also detects the structure of the type three secretion system (TTSS) inserted into the host membrane. A large variety of
molecules can also traffic through the host endocytic machinery to trigger NLRP3 and NLRP1 (see text for details). In this case, the mechanism
underlying inflammasome activation is not fully elucidated but is thought to involve NADPH oxidase-generated reactive oxygen species (ROS) or the
damage to the lysosomal membrane and the release of cathepsin B (cat B). Finally, potassium efflux (that can be triggered by the binding of ATP to the
purinergic receptors of the P2X family) also triggers NLRP3 through a mechanism likely involving ROS generation.
been proposed that NLRX1 could interact with the
antiviral protein MAVS, on the cytosolic side of the
mitochondrial outer membrane [34]. The capture of
NLRX1 by MAVS on its way to the mitochondrial matrix
in certain conditions, such as viral infection, is an inter-
esting hypothesis that awaits experimental evidence.
Functional consequences of NLR signaling athost membranesNLRs as gatekeepers of endosomal or phagosomal
trafficking
The intimate relation between host membrane dynamics
and NLR activation has been recently illustrated by the
observation that Nod ligands are internalized by clathrin-
mediated endocytosis and seem to be exported to the
cytosol in a specific manner. In the case of the Nod2
ligand MDP, studies in macrophages suggest that the
molecule travels through the endocytic machinery up to
lysosomes, where MDP is exported to the cytosol and is
www.sciencedirect.com
detected by NLR proteins [37,38]. It is likely that this site
of translocation to the cytosol is physiologically critical for
phagocytic cells; indeed, two recent reports demonstrate
that the progressive degradation and processing of bac-
teria or bacterial cell walls in the phagolysosome results in
the generation of peptidoglycan fragments that can trig-
ger either Nod2 [37] or NLRP3 [39] after cytosolic
translocation. However, the nature of the transporters
for MDP or other peptidoglycan motifs in the phagolyso-
some remains unknown. In HEK293T epithelial cells,
recent evidence demonstrated that Nod1 ligands are also
internalized by clathrin-dependent endocytosis and are
exported to the cytosol from early endosomes, in part
through the oligopeptide transporter SLC15A4 [40]. Stu-
dies in other human epithelial cells similarly identified
roles for other related transporters in mediating the trans-
port of Nod ligands. Indeed, SLC15A1 and SLC15A2
were shown to transport MDP (in Caco-2 cells) [41,42]
and iE-DAP (in upper airway epithelial cells) [43],
Current Opinion in Immunology 2010, 22:428–434
432 Host pathogens
respectively. However, in the latter cases, the precise
mechanism of internalization and location of cytosolic
export was not identified. Together, these recent findings
demonstrate that Nod-dependent activation is physio-
logically coupled with endocytic/phagocytic maturation
and bacterial cell wall degradation processes. It is con-
ceivable that the topological restriction of the cytosolic
entry site (plasma membrane, early endosomes, and pha-
golysosome) for NLR ligands might direct the nature of
the host response, such as NF-kB, caspase-1 inflamma-
some or type I interferon pathways. This concept was
indeed recently put forward in the case of TLR stimu-
lation, since the engagement of TLR4/MyD88/NF-kB
versus TLR4/TRAM/type I interferon pathways were
found to occur at the level of the plasma membrane
versus early endosomes, respectively [44].
Induction of bacterial autophagy by Nod proteins
Autophagy is a cellular process through which defective
organelles, protein aggregates or foreign material
(including microbes) are sequestered into double mem-
branes coated by proteins of the autophagic machinery, and
directed to lysosomes for destruction. Recently, the NLR
Figure 3
Nod proteins trigger the recruitment of the autophagic machinery at the
bacterial entry site. (A) Nod proteins detect invading bacteria likely
following local delivery of peptidoglycan fragments. This results in the
recruitment of ATG16L1, which in turn directs the coalescence of the
autophagic machinery at the site of bacterial entry. (B) Schematic
representation of the Nod1/2-dependent signaling cascade. While the
adaptor protein Rip2 is essential for Nod-dependent activation of NF-kB
as well as MAP kinase cascades, autophagy triggered by bacterial
invasion seems to operate in a Rip2-independent manner, likely through
the complex formed between Nod1/2 and ATG16L1.
Current Opinion in Immunology 2010, 22:428–434
proteins Nod1 and Nod2 have been shown to play a key
role in mediating bacterial autophagy [6]. Indeed, these
NLR proteins were found to interact with the autophagy-
nucleator protein ATG16L1, resulting in the recruitment
of the proteins of the autophagic machinery at the site of
bacterial entry (Figure 3). These results link Nod2 and
ATG16L1, two proteins whose genes have been associated
with CD susceptibility, therefore strongly suggesting that
improper targeting of bacteria by the autophagic machin-
ery plays a key role in CD pathogenesis. The fact that
bacteria could be targeted by Nod-dependent autophagy at
the plasma membrane before cell invasion suggests that
these NLR proteins likely detect minute amounts of
peptidoglycan delivered to the cytosol by the type III
secretion system. Moreover, the rupturing of the mem-
brane during bacterial invasion seems to provide a signaling
platform that potentially initializes both autophagy and
NLR activation [45]. This illustrates another important
role of Nod-dependent activation at host membranes. In
agreement with these observations, Nod2-dependent
induction of autophagy in human dendritic cells has been
shown to be critical for bacterial targeting to the lysosome
and for subsequent optimal antigen presentation on the
major histocompatibility (MHC) complex II [46].
Concluding remarksThe functional importance of NLRs as cytosolic sentinels
of the innate immune system at the vicinity of host
membranes is an emerging concept that is supported
by numerous experimental evidence, as presented in this
review. Linking NLR activation to host membrane
patrolling likely confers two main advantages: (i) it allows
safe and rapid response to microbes and danger, since
cytosolic threats necessarily need to cross at least one host
membrane, and membrane rupture, damage or electro-
chemical alteration are common events triggered by
bacteria, viruses, parasites or danger signals. (ii) It allows
NLR activation in a restricted area of the cell where
signals to be detected (ROS, K+ efflux, microbial motifs
translocated through a specific secretion system, material
released from the lysosome) display their highest con-
centration, thus ensuring the activation threshold is effi-
ciently met. This last point likely explains how Nod1 can
induce innate immune response to extracellular bacterial
pathogens [47,48], or direct the recruitment of the autop-
hagic machinery at the site of bacterial entry, when
bacteria are still extracellular [6]. In the case of Helico-bacter pylori, it was demonstrated that peptidoglycan is
translocated to the host cell cytosol via the type IV
secretion system, resulting in Nod1-dependent inflam-
matory signaling [48].
Finally, are there data to show NLR activation at sites
distant from host membranes? Paradoxically, for these
cytosolic sensors, direct evidence for this mode of acti-
vation is lacking. Indeed, it remains unknown if for
instance intracellular bacteria, moving freely in the host
www.sciencedirect.com
Sentinels at host membranes Philpott and Girardin 433
cytosol (as is the case for Shigella or Listeria), can be
efficiently detected by NLRs, to trigger inflammatory
signaling or autophagy induction. Answering this crucial
question will require the development of reactive probes
to allow visualization and measurement of NLR acti-
vation in live cells.
AcknowledgementsWe apologize to those whose original work was not cited in this review,because of space limitations. Research in the laboratories of D.J.P. andS.E.G. is supported by funding from the Canadian Institutes of HealthResearch (to S.E.G. and D.J.P.), Crohn’s and Colitis Foundation of Canada(S.E.G.), Burrows Wellcome Fund (S.E.G.) and Howard Hughes MedicalInstitutes (D.J.P.).
References
1. Takeuchi O, Akira S: Pattern recognition receptors andinflammation. Cell 2010, 140:805-820.
2. Fritz JH, Ferrero RL, Philpott DJ, Girardin SE: Nod-like proteins inimmunity, inflammation and disease. Nat Immunol 2006,7:1250-1257.
3. Kanneganti TD, Lamkanfi M, Nunez G: Intracellular NOD-likereceptors in host defense and disease. Immunity 2007,27:549-559.
4. Brodsky IE, Monack D: NLR-mediated control of inflammasomeassembly in the host response against bacterial pathogens.Semin Immunol 2009, 21:199-207.
5. Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y,Mimuro H, Inohara N, Sasakawa C, Nunez G: Differentialregulation of caspase-1 activation, pyroptosis, and autophagyvia Ipaf and ASC in Shigella-infected macrophages. PLoSPathog 2007, 3:e111.
6. Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG,Magalhaes JG, Yuan L, Soares F, Chea E, Le Bourhis L et al.: Nod1and Nod2 direct autophagy by recruiting ATG16L1 to theplasma membrane at the site of bacterial entry. Nat Immunol2010, 11:55-62.
7. Fink SL, Bergsbaken T, Cookson BT: Anthrax lethal toxin andSalmonella elicit the common cell death pathway ofcaspase-1-dependent pyroptosis via distinct mechanisms.Proc Natl Acad Sci USA 2008, 105:4312-4317.
8. Willingham SB, Bergstralh DT, O’Connor W, Morrison AC,Taxman DJ, Duncan JA, Barnoy S, Venkatesan MM, Flavell RA,Deshmukh M et al.: Microbial pathogen-induced necrotic celldeath mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe 2007, 2:147-159.
9. Miao EA, Andersen-Nissen E, Warren SE, Aderem A: TLR5 andIpaf: dual sensors of bacterial flagellin in the innate immunesystem. Semin Immunopathol 2007, 29:275-288.
10. Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG,Warren SE, Leaf IA, Aderem A: Innate immune detection of thetype III secretion apparatus through the NLRC4inflammasome. Proc Natl Acad Sci USA 2010, 107:3076-3080.
11. Benko S, Philpott DJ, Girardin SE: The microbial and dangersignals that activate Nod-like receptors. Cytokine 2008,43:368-373.
12. Schroder K, Tschopp J: The inflammasomes. Cell 2010,140:821-832.
13. Latz E: The inflammasomes: mechanisms of activation andfunction. Curr Opin Immunol 2010, 22:28-33.
14. Tschopp J, Schroder K: NLRP3 inflammasome activation: theconvergence of multiple signalling pathways on ROSproduction? Nat Rev Immunol 2010, 10:210-215.
15. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J: Thioredoxin-interacting protein links oxidative stress to inflammasomeactivation. Nat Immunol 2010, 11:136-140.
www.sciencedirect.com
16. Fukata M, Vamadevan AS, Abreu MT: Toll-like receptors (TLRs)and Nod-like receptors (NLRs) in inflammatory disorders.Semin Immunol 2009, 21:242-253.
17. Geddes K, Magalhaes JG, Girardin SE: Unleashing thetherapeutic potential of NOD-like receptors. Nat Rev DrugDiscov 2009, 8:465-479.
18. Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M,Body-Malapel M, Inohara N, Nunez G: RICK/RIP2 mediatesinnate immune responses induced through Nod1 and Nod2but not TLRs. J Immunol 2007, 178:2380-2386.
19. Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E,Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC:Reconstituted NALP1 inflammasome reveals two-stepmechanism of caspase-1 activation. Mol Cell 2007, 25:713-724.
20. Barnich N, Aguirre JE, Reinecker HC, Xavier R, Podolsky DK:Membrane recruitment of NOD2 in intestinal epithelial cells isessential for nuclear factor-{kappa}B activation in muramyldipeptide recognition. J Cell Biol 2005, 170:21-26.
21. Lecine P, Esmiol S, Metais JY, Nicoletti C, Nourry C, McDonald C,Nunez G, Hugot JP, Borg JP, Ollendorff V: The NOD2-RICKcomplex signals from the plasma membrane. J Biol Chem2007, 282:15197-15207.
22. Kufer TA, Kremmer E, Adam AC, Philpott DJ, Sansonetti PJ: Thepattern-recognition molecule Nod1 is localized at the plasmamembrane at sites of bacterial interaction. Cell Microbiol 2008,10:477-486.
23. Legrand-Poels S, Kustermans G, Bex F, Kremmer E, Kufer TA,Piette J: Modulation of Nod2-dependent NF-kappaBsignaling by the actin cytoskeleton. J Cell Sci 2007,120:1299-1310.
24. Kufer TA, Kremmer E, Banks DJ, Philpott DJ: Role for erbinin bacterial activation of Nod2. Infect Immun 2006,74:3115-3124.
25. McDonald C, Chen FF, Ollendorff V, Ogura Y, Marchetto S,Lecine P, Borg JP, Nunez G: A role for Erbin in the regulation ofNod2-dependent NF-kappaB signaling. J Biol Chem 2005,280:40301-40309.
26. Eitel J, Krull M, Hocke AC, N’Guessan PD, Zahlten J, Schmeck B,Slevogt H, Hippenstiel S, Suttorp N, Opitz B: Beta-PIX and Rac1GTPase mediate trafficking and negative regulation of NOD2.J Immunol 2008, 181:2664-2671.
27. Fukazawa A, Alonso C, Kurachi K, Gupta S, Lesser CF,McCormick BA, Reinecker HC: GEF-H1 mediated control ofNOD1 dependent NF-kappaB activation by Shigella effectors.PLoS Pathog 2008, 4:e1000228.
28. Lipinski S, Till A, Sina C, Arlt A, Grasberger H, Schreiber S,Rosenstiel P: DUOX2-derived reactive oxygen species areeffectors of NOD2-mediated antibacterial responses. J Cell Sci2009, 122:3522-3530.
29. Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K,Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM:Cryopyrin activates the inflammasome in response to toxinsand ATP. Nature 2006, 440:228-232.
30. Petrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J:Activation of the NALP3 inflammasome is triggered by lowintracellular potassium concentration. Cell Death Differ 2007,14:1583-1589.
31. Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N,Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A et al.:Cytosolic flagellin requires Ipaf for activation of caspase-1 andinterleukin 1beta in salmonella-infected macrophages.Nat Immunol 2006, 7:576-582.
32. Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW,Miller SI, Aderem A: Cytoplasmic flagellin activates caspase-1and secretion of interleukin 1beta via Ipaf. Nat Immunol 2006,7:569-575.
33. Lightfield KL, Persson J, Brubaker SW, Witte CE, von Moltke J,Dunipace EA, Henry T, Sun YH, Cado D, Dietrich WF et al.: Criticalfunction for Naip5 in inflammasome activation by a conserved
Current Opinion in Immunology 2010, 22:428–434
434 Host pathogens
carboxy-terminal domain of flagellin. Nat Immunol 2008,9:1171-1178.
34. Moore CB, Bergstralh DT, Duncan JA, Lei Y, Morrison TE,Zimmermann AG, Accavitti-Loper MA, Madden VJ, Sun L, Ye Zet al.: NLRX1 is a regulator of mitochondrial antiviral immunity.Nature 2008, 451:573-577.
35. Tattoli I, Carneiro LA, Jehanno M, Magalhaes JG, Shu Y,Philpott DJ, Arnoult D, Girardin SE: NLRX1 is a mitochondrialNOD-like receptor that amplifies NF-kappaB and JNKpathways by inducing reactive oxygen species production.EMBO Rep 2008, 9:293-300.
36. Arnoult D, Soares F, Tattoli I, Castanier C, Philpott DJ, Girardin SE:An N-terminal addressing sequence targets NLRX1 to themitochondrial matrix. J Cell Sci 2009, 122:3161-3168.
37. Herskovits AA, Auerbuch V, Portnoy DA: Bacterial ligandsgenerated in a phagosome are targets of the cytosolic innateimmune system. PLoS Pathog 2007, 3:e51.
38. Marina-Garcia N, Franchi L, Kim YG, Hu Y, Smith DE, Boons GJ,Nunez G: Clathrin- and dynamin-dependent endocyticpathway regulates muramyl dipeptide internalization andNOD2 activation. J Immunol 2009, 182:4321-4327.
39. Shimada T, Park BG, Wolf AJ, Brikos C, Goodridge HS, Becker CA,Reyes CN, Miao EA, Aderem A, Gotz F et al.: Staphylococcusaureus evades lysozyme-based peptidoglycan digestion thatlinks phagocytosis, inflammasome activation, and IL-1betasecretion. Cell Host Microbe 2010, 7:38-49.
40. Lee J, Tattoli I, Wojtal KA, Vavricka SR, Philpott DJ, Girardin SE:pH-dependent internalization of muramyl peptides from earlyendosomes enables Nod1 and Nod2 signaling. J Biol Chem2009, 284:23818-23829.
41. Ismair MG, Vavricka SR, Kullak-Ublick GA, Fried M,Mengin-Lecreulx D, Girardin SE: hPepT1 selectively transports
Current Opinion in Immunology 2010, 22:428–434
muramyl dipeptide but not Nod1-activating muramyl peptides.Can J Physiol Pharmacol 2006, 84:1313-1319.
42. Vavricka SR, Musch MW, Chang JE, Nakagawa Y, Phanvijhitsiri K,Waypa TS, Merlin D, Schneewind O, Chang EB: hPepT1transports muramyl dipeptide, activating NF-kappaB andstimulating IL-8 secretion in human colonic Caco2/bbe cells.Gastroenterology 2004, 127:1401-1409.
43. Swaan PW, Bensman T, Bahadduri PM, Hall MW, Sarkar A, Bao S,Khantwal CM, Ekins S, Knoell DL: Bacterial peptide recognitionand immune activation facilitated by human peptidetransporter PEPT2. Am J Respir Cell Mol Biol 2008, 39:536-542.
44. Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R: TRAMcouples endocytosis of Toll-like receptor 4 to the induction ofinterferon-beta. Nat Immunol 2008, 9:361-368.
45. Dupont N, Lacas-Gervais S, Bertout J, Paz I, Freche B, VanNhieu GT, van der Goot FG, Sansonetti PJ, Lafont F: Shigellaphagocytic vacuolar membrane remnants participate in thecellular response to pathogen invasion and are regulated byautophagy. Cell Host Microbe 2009, 6:137-149.
46. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P,Ferguson DJ, Campbell BJ, Jewell D, Simmons A: NOD2stimulation induces autophagy in dendritic cells influencingbacterial handling and antigen presentation. Nat Med 2010,16:90-97.
47. Travassos LH, Carneiro LA, Girardin SE, Boneca IG, Lemos R,Bozza MT, Domingues RC, Coyle AJ, Bertin J, Philpott DJ et al.:Nod1 participates in the innate immune response toPseudomonas aeruginosa. J Biol Chem 2005.
48. Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP,Athman R, Memet S, Huerre MR, Coyle AJ et al.: Nod1 respondsto peptidoglycan delivered by the Helicobacter pylori cagpathogenicity island. Nat Immunol 2004, 5:1166-1174.
www.sciencedirect.com
top related