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  • 1. Available online at www.sciencedirect.comNod-like receptors: sentinels at host membranesDana J Philpott1 and Stephen E Girardin2Innate immune detection of danger signals and microbial motifs transduction cascades, which include the pro-inflamma-is achieved by distinct families of pattern recognition tory NF-kB (for Nod1 and Nod2) [2,3] and the caspase-1molecules. These include the membrane-anchored Toll-like inflammasome (for NLRC4, NLRP3 and NLRP1) path-receptors (TLRs), as well as cytosolic Nod-like receptors ways [4] as well as activation of autophagy (Nod1, Nod2(NLRs) and Rig-I-like receptors (RLRs). The precise mode of and NLRC4) [5,6] and cell death (including NLRC4,NLR activation in the host cytosol remains poorly defined, as NLRP1 and NLRP3) [5,7,8].evidence of direct interaction between NLRs and danger- ormicrobial-associated molecular patterns remains elusive. In the past few years, the identification of the nature ofHowever, a number of convergent observations now suggest the molecular patterns detected by NLRs has been thethat activation of some NLRs occurs at the level of host subject of intense investigations, and the key role ofmembranes or as a consequence of membrane damage. This NLRs in the cytosolic detection of various MAMPsreview focuses on this emerging theme and discusses the and DAMPs is clearly emerging. Nod1 and Nod2 detectfunctional consequences of innate immune sensing at the specific structures within bacterial peptidoglycan [2], andvicinity of the membrane. NLRC4 senses bacterial flagellin [9] as well as the bac-Addresses terial type III secretion apparatus [10]. The inflamma-1 Department of Immunology, University of Toronto, Toronto, Canada some-triggering protein NLRP3 was shown to detect a2 Department of Laboratory Medicine and Pathobiology, University of wide array of molecules, including ATP, potassium efflux,Toronto, Toronto, Canada muramyl dipeptide (MDP), bacterial toxins, xenocom-Corresponding authors: Girardin, Stephen E pounds (silica, asbestos, and aluminium hydroxide), viral(stephen.girardin@utoronto.ca) 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 Current Opinion in Immunology 2010, 22:428–434 lethal toxin, MDP, and potassium efflux. The extremely This review comes from a themed issue on diverse repertoire of the molecular triggers activating the Host pathogens caspase-1 inflammasome led to the hypothesis that Edited by Adolfo Garcia-Sastre and Philippe Sansonetti NLRP proteins must in fact be activated by common upstream cellular events [12–14]. The NADPH-depend- Available online 3rd June 2010 ent generation of reactive oxygen species (ROS) or rup- 0952-7915/$ – see front matter ture of the lysosomal membrane could represent such # 2010 Elsevier Ltd. All rights reserved. common activators of the caspase-1 inflammasome. In DOI 10.1016/j.coi.2010.04.010 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].Innate immunity relies on the detection of danger- andmicrobial-associated molecular patterns (DAMPs and The interest in NLR biology is also driven by the strikingMAMPs, respectively) by several families of secreted association between mutations or polymorphisms in NLRor cellular pattern-recognition molecules (PRMs). Several or NLR-associated genes and human inflammatory dis-classes of cellular PRMS are directly responsible for the orders, which underscores the importance of this family ininduction of signal transduction pathways that shape the the control of inflammation [16,17]. In particular, Nod2innate immune response, and these include the type I has been identified as the first susceptibility gene fortransmembrane molecules of the Toll-like receptor Crohn’s disease (CD) and Blau syndrome, and mutations(TLR) family as well as the cytosolic Nod-like receptors in Nlrp3 (also known as Cryopyrin or Cias1) are associated(NLRs) and Rig-I-like receptors (RLRs) [1]. with several rare autoinflammatory disorders, including Muckle–Wells syndrome, chronic infantile neurologicalThe NLR family cutaneous and articular syndrome (CINCA) and familialNLRs are defined by the juxtaposition of a central cold urticaria (FCU), and common variants in Nlrp3 have(NACHT) domain and C-terminal leucine-rich repeat also been recently associated with CD [16,17]. In(LRR) domain [2,3]. Twenty-two NLR proteins are pre- addition, polymorphisms in Nod1 have been associatedsent in the human genome, which are further grouped with asthma and atopic eczema, and Nlrp1 was identifiedinto subfamilies on the basis of their N-terminal region. as a susceptibility gene for vitiligo, Addison’s disease andUpon activation, NLR proteins trigger a number of signal type I diabetes [16,17].Current Opinion in Immunology 2010, 22:428–434 www.sciencedirect.com
  • 2. Sentinels at host membranes Philpott and Girardin 429Signal transduction cascades triggered by NLR engage- demonstrated that enforced targeting of Rip2 to thement have been studied in detail. A general common plasma membrane was sufficient to trigger NF-kB [21].mechanism of activation likely requires the (homo- or Similar results were also reported for Nod1, as both Nod1hetero-) oligomerization of NLR proteins, resulting in the and the IKKg subunit of the IKK complex, critical forrecruitment of adaptor proteins, such as Rip2 for Nod1 NF-kB activation, were found enriched at the plasmaand Nod2, or ASC for NLRC4, NLRP1 and NLRP3 [2,3]. membrane, at the site of bacterial entry [22].Rip2 is essential for mediating Nod1- and Nod2-depend-ent activation of NF-kB and MAPK signaling [18], but is The consequence of targeting Nod protein to the plasmadispensable for the Nod-driven recruitment of the autop- membrane is likely complex and dynamic. Indeed, relo-hagosome at the site of bacterial entry in murine embryo- calization of Nod2 from a Triton-X-100 insoluble tonic fibroblasts [6]. The exact requirement of ASC for soluble fractions with cytochalasin D, or exclusion ofNLRP and NLRC4 signaling is more complex, since this Nod2 from membrane ruffles, were found to correlateadaptor protein was found to be either essential or dis- with enhanced capacity to trigger NF-kB pathways [23],pensable in multiple models of NLR-dependent acti- suggesting that, in basal conditions, Nod-dependentvation of the caspase-1 inflammasome [12]. activity might be locked out by membrane- or actin- associated cofactors. In agreement for this, two indepen-The nature of the events occurring upstream of NLR dent studies identified the membrane-associated proteinengagement, and in particular the exact mode of the Erbin as a Nod2-interacting protein, and demonstrateddetection of MAMPs or DAMPs by NLRs, remains less that Erbin acted as a negative modulator of Nod2-de-understood. In the vast majority of cases, direct detection pendent pathways [24,25]. Other membrane-associatedor interaction between NLRs and either MAMPs or proteins have been shown to interact with Nod proteinsDAMPs has not been demonstrated. An exception to this and to modulate their function. The Rho GTPase Rac1,was a recent study in which the authors performed an in which is essential for the regulation of membrane rufflingvitro reconstitution of the NLRP1 inflammasome and and is also a component of the NADPH oxidase complex,demonstrated oligomerization of NLRP1 and caspase-1 was found to interact with Nod2 and to negativelythrough addition of MDP [19], therefore suggesting the regulate its function [23,26]. In contrast, the guanineexistence of a direct interaction between NLRP1 and exchange factor GEF-H1, which plays important rolesMDP. In the case of NLRP3, as discussed above, it is in RhoA activation in the context of Shigella invasion inbelieved that secondary cellular events such as ROS- non-myeloid cells, was found to interact with Nod1 andinduced modifications or lysosomal damage might play positively modulate its function [27]. Finally, the proteina key role in activation [12–14]. The cytosolic sub-cellular Duox2 of the NADPH oxidase complex was found tolocalization where NLR engagement occurs is also not interact with Nod2 and to potentiate its function [28].clearly established, because of the lack of sensitive tools The opposite effect of two members of the NADPHto probe NLR activation by microscopy techniques. oxidase complex (Rac1 and Duox2) on Nod2-dependentHowever, recent biochemical evidence points to a tight pathway remains unclear, but might reflect the morerelation between NLR activation and sub-cellular vicinity general impact of membrane targeting on Nod activity,to plasma or internal membranes. An intriguing possib- acting as a negative or positive modulator of Nod functionility would suggest that NLR localization at membranes is in resting versus ROS-generating or membrane-remodel-not coincidental with NLR activation but actually a ing conditions, respectively (Figures 1 and 2).prerequisite for physiological activation. The followingdiscussion reviews this hypothesis. NLRP1 and NLRP3 The functional relation between the activity of NLRP3Evidence for the activation of NLRs at host and NLRP1 and host membranes is indirectly inferred bymembranes the nature of the MAMPs or DAMPs that they detect.Nod1 and Nod2 Indeed, the fact that potassium efflux at the plasmaThe first indication that NLRs function at host mem- membrane is sufficient to trigger NLRP3 and NLRP1branes came from a study by Barnich et al. who demon- activation [29,30] is a strong indication that these NLRsstrated that Nod2-dependent responses to MDP are activated at the vicinity of the plasma membrane,correlated with the capacity of the protein to localize where the dynamic variation of [K+] is the greatest.to the plasma membrane [20]. Importantly, the authors Similarly, NADPH oxidase-dependent ROS levels likelyidentified that the C-terminal end of the protein was diffuse poorly into the cytosolic space because of theirresponsible for membrane targeting, therefore explaining unstable nature and the presence of a number of bufferingthe defective MDP sensing capacity of the CD-associated cellular antioxidants. Therefore, NADPH-generatedNod2 variant Nod2 3020insC, which lacks the last 33 ROS concentration must display a dynamic gradientCOOH-terminal amino acids of the protein. A recent resulting from the flux of their generation, with thestudy further validated these observations by showing highest concentration found at the vicinity of the plasmathat Rip2 was also found at the plasma membrane, and or phagocytic membranes. Another interesting possibilitywww.sciencedirect.com Current Opinion in Immunology 2010, 22:428–434
  • 3. 430 Host pathogensFigure 1Activation of Nod1 and Nod2 at host membranes. Nod proteins can detect peptidoglycan fragments produced in host phagosome or phagolysosomeduring degradation of phagocytosed bacteria. The nature of the transporters involved in the translocation of peptidoglycan from the phagolysosome tothe cytosol remains unknown. Peptidoglycan fragments in the extracellular milieu can also enter cells by endocytosis. In HEK293T cells, peptidoglycanfragments translocate to the cytosol at least in part through the oligopeptide transporter SLC15A4. Nod proteins interact with membrane-associatedproteins GEF-H1, Erbin, as well as Rac1 and Duox2 from the NADPH oxidase complex. Nod1 and Nod2 also detect invading bacteria and trigger therecruitment of the autophagic machinery (see also Figure 3).would be that NLRP proteins could directly detect this, NLRC4 has been recently shown to detect directlymembrane damage or leakage. This idea is consistent the basal body rod component of the type III secretionwith the fact that several membrane toxins that insert into system apparatus of several Gram-negative bacteria, in-host membranes, such as listeriolysin O, streptolysin O, a- cluding Salmonella typhimurium, Shigella flexneri and Pseu-hemolysin or the anthrax lethal toxin were found to domonas aeruginosa. It must be noted that Naip5, anothertrigger NLRP-dependent caspase-1 inflammasomes NLR protein previously identified as a critical protein[12,13]. In addition, multiple lines of evidence point to implicated in the restriction of Legionella growth in macro-a role of lysosomal damage and cytosolic leakage of phages, was also shown to participate in intracellularcathepsin B in NLRP3 activation [13], suggesting that flagellin detection, together with NLRC4 [33].NLRP protein may act as intracellular sensors of hostmembrane integrity. NLRX1 NLRX1 localizes to mitochondria and is the only knownNLRC4 NLR protein that targets specifically a cellular organelleNLRC4 was found to detect intracellular bacterial fla- [34,35]. Recent evidence demonstrated that NLRX1gellin [31,32]. While this detection could in theory occur translocates to the mitochondrial matrix via its N-terminalanywhere in the host cytosol in the case of flagellated addressing sequence and biochemical studies identifiedbacteria that escape the phagocytic vacuole, it is inter- that the protein associates with the mitochondrial inneresting to note that NLRC4 activation by Salmonella and membrane, at least in part, through its interaction withLegionella requires both flagellin and functional type III or UQCRC2, a matrix-exposed core component of the com-Type IV secretion systems, which insert into host mem- plex III of the respiratory chain [36]. It is possible that thisbranes [31,32]. Together, these observations suggest that interaction contributes to the capacity of NLRX1 tothe detection of flagellin by NLRC4 might be functional regulate mitochondrial ROS generation, as previouslyin the context of membrane damage. In agreement with demonstrated by over-expression studies. Finally, it hasCurrent Opinion in Immunology 2010, 22:428–434 www.sciencedirect.com
  • 4. Sentinels at host membranes Philpott and Girardin 431Figure 2Activation of the inflammasome-triggering NLR proteins at host membranes. Bacterial processing in phagosome or phagolysosome generatesmolecules (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 ofmolecules can also traffic through the host endocytic machinery to trigger NLRP3 and NLRP1 (see text for details). In this case, the mechanismunderlying inflammasome activation is not fully elucidated but is thought to involve NADPH oxidase-generated reactive oxygen species (ROS) or thedamage 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 thepurinergic receptors of the P2X family) also triggers NLRP3 through a mechanism likely involving ROS generation.been proposed that NLRX1 could interact with the detected by NLR proteins [37,38]. It is likely that this siteantiviral protein MAVS, on the cytosolic side of the of translocation to the cytosol is physiologically critical formitochondrial outer membrane [34]. The capture of phagocytic cells; indeed, two recent reports demonstrateNLRX1 by MAVS on its way to the mitochondrial matrix that the progressive degradation and processing of bac-in certain conditions, such as viral infection, is an inter- teria or bacterial cell walls in the phagolysosome results inesting hypothesis that awaits experimental evidence. the generation of peptidoglycan fragments that can trig- ger either Nod2 [37] or NLRP3 [39] after cytosolicFunctional consequences of NLR signaling at translocation. However, the nature of the transportershost membranes for MDP or other peptidoglycan motifs in the phagolyso-NLRs as gatekeepers of endosomal or phagosomal some remains unknown. In HEK293T epithelial cells,trafficking recent evidence demonstrated that Nod1 ligands are alsoThe intimate relation between host membrane dynamics internalized by clathrin-dependent endocytosis and areand NLR activation has been recently illustrated by the exported to the cytosol from early endosomes, in partobservation that Nod ligands are internalized by clathrin- through the oligopeptide transporter SLC15A4 [40]. Stu-mediated endocytosis and seem to be exported to the dies in other human epithelial cells similarly identifiedcytosol in a specific manner. In the case of the Nod2 roles for other related transporters in mediating the trans-ligand MDP, studies in macrophages suggest that the port of Nod ligands. Indeed, SLC15A1 and SLC15A2molecule travels through the endocytic machinery up to were shown to transport MDP (in Caco-2 cells) [41,42]lysosomes, where MDP is exported to the cytosol and is and iE-DAP (in upper airway epithelial cells) [43],www.sciencedirect.com Current Opinion in Immunology 2010, 22:428–434
  • 5. 432 Host pathogensrespectively. However, in the latter cases, the precise proteins Nod1 and Nod2 have been shown to play a keymechanism of internalization and location of cytosolic role in mediating bacterial autophagy [6]. Indeed, theseexport was not identified. Together, these recent findings NLR proteins were found to interact with the autophagy-demonstrate that Nod-dependent activation is physio- nucleator protein ATG16L1, resulting in the recruitmentlogically coupled with endocytic/phagocytic maturation of the proteins of the autophagic machinery at the site ofand bacterial cell wall degradation processes. It is con- bacterial entry (Figure 3). These results link Nod2 andceivable that the topological restriction of the cytosolic ATG16L1, two proteins whose genes have been associatedentry site (plasma membrane, early endosomes, and pha- with CD susceptibility, therefore strongly suggesting thatgolysosome) for NLR ligands might direct the nature of improper targeting of bacteria by the autophagic machin-the host response, such as NF-kB, caspase-1 inflamma- ery plays a key role in CD pathogenesis. The fact thatsome or type I interferon pathways. This concept was bacteria could be targeted by Nod-dependent autophagy atindeed recently put forward in the case of TLR stimu- the plasma membrane before cell invasion suggests thatlation, since the engagement of TLR4/MyD88/NF-kB these NLR proteins likely detect minute amounts ofversus TLR4/TRAM/type I interferon pathways were peptidoglycan delivered to the cytosol by the type IIIfound to occur at the level of the plasma membrane secretion system. Moreover, the rupturing of the mem-versus early endosomes, respectively [44]. brane during bacterial invasion seems to provide a signaling platform that potentially initializes both autophagy andInduction of bacterial autophagy by Nod proteins NLR activation [45]. This illustrates another importantAutophagy is a cellular process through which defective role of Nod-dependent activation at host membranes. Inorganelles, protein aggregates or foreign material agreement with these observations, Nod2-dependent(including microbes) are sequestered into double mem- induction of autophagy in human dendritic cells has beenbranes coated by proteins of the autophagic machinery, and shown to be critical for bacterial targeting to the lysosomedirected to lysosomes for destruction. Recently, the NLR and for subsequent optimal antigen presentation on the major histocompatibility (MHC) complex II [46].Figure 3 Concluding remarks The 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 IVNod proteins trigger the recruitment of the autophagic machinery at thebacterial entry site. (A) Nod proteins detect invading bacteria likely secretion system, resulting in Nod1-dependent inflam-following local delivery of peptidoglycan fragments. This results in the matory signaling [48].recruitment of ATG16L1, which in turn directs the coalescence of theautophagic machinery at the site of bacterial entry. (B) Schematic Finally, are there data to show NLR activation at sitesrepresentation of the Nod1/2-dependent signaling cascade. While the distant from host membranes? Paradoxically, for theseadaptor protein Rip2 is essential for Nod-dependent activation of NF-kBas well as MAP kinase cascades, autophagy triggered by bacterial cytosolic sensors, direct evidence for this mode of acti-invasion seems to operate in a Rip2-independent manner, likely through vation is lacking. Indeed, it remains unknown if forthe complex formed between Nod1/2 and ATG16L1. instance intracellular bacteria, moving freely in the hostCurrent Opinion in Immunology 2010, 22:428–434 www.sciencedirect.com
  • 6. Sentinels at host membranes Philpott and Girardin 433cytosol (as is the case for Shigella or Listeria), can be 16. Fukata M, Vamadevan AS, Abreu MT: Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders.efficiently detected by NLRs, to trigger inflammatory Semin Immunol 2009, 21:242-253.signaling or autophagy induction. Answering this crucial 17. Geddes K, Magalhaes JG, Girardin SE: Unleashing thequestion will require the development of reactive probes therapeutic potential of NOD-like receptors. Nat Rev Drugto allow visualization and measurement of NLR acti- Discov 2009, 8:465-479.vation in live cells. 18. Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M, Body-Malapel M, Inohara N, Nunez G: RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2Acknowledgements but not TLRs. J Immunol 2007, 178:2380-2386.We apologize to those whose original work was not cited in this review,because of space limitations. Research in the laboratories of D.J.P. and 19. Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC:S.E.G. is supported by funding from the Canadian Institutes of Health Reconstituted NALP1 inflammasome reveals two-stepResearch (to S.E.G. and D.J.P.), Crohn’s and Colitis Foundation of Canada mechanism of caspase-1 activation. Mol Cell 2007, 25:713-724.(S.E.G.), Burrows Wellcome Fund (S.E.G.) and Howard Hughes MedicalInstitutes (D.J.P.). 20. Barnich N, Aguirre JE, Reinecker HC, Xavier R, Podolsky DK: Membrane recruitment of NOD2 in intestinal epithelial cells is essential for nuclear factor-{kappa}B activation in muramylReferences dipeptide recognition. J Cell Biol 2005, 170:21-26.1. Takeuchi O, Akira S: Pattern recognition receptors and 21. Lecine P, Esmiol S, Metais JY, Nicoletti C, Nourry C, McDonald C, inflammation. Cell 2010, 140:805-820. 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