Migration of immune cells is orchestrated by a fine balance of cytokine and chemokine responses. During Leishmania macrophage interaction, either pro inflammatory or anti-inflammatory cytokines are produced, having an impact in the establishment of infection and further clinical outcome (Navas et al. 2014). Toll like receptors, GPCRs such as the purinergic receptors P2YRs, complement receptor 3A and interleukin receptor 15 amongst others, have been associated with the production of pro inflammatory cytokines (Lai and Gallo 2012 & Cekic et al. 2016). A strong pro inflammatory response in the acute phase of the infection helps to control the parasite load when the recruited cells enhance microbiocidal mechanisms. However, alterations in the chemokine network may contribute to uncontrolled immune responses that can modulate parasite survival and promote or mitigate the associated immunopathology, thereby influencing the outcome of infection (Navas et al. 2014).
View original pathway at Reactome.
Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A, Quintal L, Sekut L, Talanian R, Paskind M, Wong W, Kamen R, Tracey D, Allen H.; ''Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production.''; PubMedEurope PMCScholia
Lemmens R, Vanduffel L, Kittel A, Beaudoin AR, Benrezzak O, Sévigny J.; ''Distribution, cloning, and characterization of porcine nucleoside triphosphate diphosphohydrolase-1.''; PubMedEurope PMCScholia
Fang M, Shen Z, Huang S, Zhao L, Chen S, Mak TW, Wang X.; ''The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway.''; PubMedEurope PMCScholia
Cekic C, Linden J.; ''Purinergic regulation of the immune system.''; PubMedEurope PMCScholia
Walker NP, Talanian RV, Brady KD, Dang LC, Bump NJ, Ferenz CR, Franklin S, Ghayur T, Hackett MC, Hammill LD.; ''Crystal structure of the cysteine protease interleukin-1 beta-converting enzyme: a (p20/p10)2 homodimer.''; PubMedEurope PMCScholia
Campbell EJ, Silverman EK, Campbell MA.; ''Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity.''; PubMedEurope PMCScholia
Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA, Hayashi N, Higashino K, Okamura H, Nakanishi K, Kurimoto M, Tanimoto T, Flavell RA, Sato V, Harding MW, Livingston DJ, Su MS.; ''Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme.''; PubMedEurope PMCScholia
Misumi Y, Ogata S, Ohkubo K, Hirose S, Ikehara Y.; ''Primary structure of human placental 5'-nucleotidase and identification of the glycolipid anchor in the mature form.''; PubMedEurope PMCScholia
Martinon F, Burns K, Tschopp J.; ''The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.''; PubMedEurope PMCScholia
Thompson LF, Ruedi JM, Low MG.; ''Purification of 5'-nucleotidase from human placenta after release from plasma membranes by phosphatidylinositol-specific phospholipase C.''; PubMedEurope PMCScholia
Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT.; ''The NALP3 inflammasome is involved in the innate immune response to amyloid-beta.''; PubMedEurope PMCScholia
Srinivasula SM, Poyet JL, Razmara M, Datta P, Zhang Z, Alnemri ES.; ''The PYRIN-CARD protein ASC is an activating adaptor for caspase-1.''; PubMedEurope PMCScholia
Zimmermann H.; ''5'-Nucleotidase: molecular structure and functional aspects.''; PubMedEurope PMCScholia
Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J.; ''Thioredoxin-interacting protein links oxidative stress to inflammasome activation.''; PubMedEurope PMCScholia
Mulero JJ, Yeung G, Nelken ST, Ford JE.; ''CD39-L4 is a secreted human apyrase, specific for the hydrolysis of nucleoside diphosphates.''; PubMedEurope PMCScholia
Kauffenstein G, Drouin A, Thorin-Trescases N, Bachelard H, Robaye B, D'Orléans-Juste P, Marceau F, Thorin E, Sévigny J.; ''NTPDase1 (CD39) controls nucleotide-dependent vasoconstriction in mouse.''; PubMedEurope PMCScholia
Kukulski F, Lévesque SA, Lavoie EG, Lecka J, Bigonnesse F, Knowles AF, Robson SC, Kirley TL, Sévigny J.; ''Comparative hydrolysis of P2 receptor agonists by NTPDases 1, 2, 3 and 8.''; PubMedEurope PMCScholia
Dowds TA, Masumoto J, Chen FF, Ogura Y, Inohara N, Núñez G.; ''Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product.''; PubMedEurope PMCScholia
Yamasaki K, Muto J, Taylor KR, Cogen AL, Audish D, Bertin J, Grant EP, Coyle AJ, Misaghi A, Hoffman HM, Gallo RL.; ''NLRP3/cryopyrin is necessary for interleukin-1beta (IL-1beta) release in response to hyaluronan, an endogenous trigger of inflammation in response to injury.''; PubMedEurope PMCScholia
Laudisi F, Spreafico R, Evrard M, Hughes TR, Mandriani B, Kandasamy M, Morgan BP, Sivasankar B, Mortellaro A.; ''Cutting edge: the NLRP3 inflammasome links complement-mediated inflammation and IL-1β release.''; PubMedEurope PMCScholia
Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC.; ''Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression.''; PubMedEurope PMCScholia
Shoham NG, Centola M, Mansfield E, Hull KM, Wood G, Wise CA, Kastner DL.; ''Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway.''; PubMedEurope PMCScholia
Richards N, Schaner P, Diaz A, Stuckey J, Shelden E, Wadhwa A, Gumucio DL.; ''Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis.''; PubMedEurope PMCScholia
Ames RS, Li Y, Sarau HM, Nuthulaganti P, Foley JJ, Ellis C, Zeng Z, Su K, Jurewicz AJ, Hertzberg RP, Bergsma DJ, Kumar C.; ''Molecular cloning and characterization of the human anaphylatoxin C3a receptor.''; PubMedEurope PMCScholia
Asgari E, Le Friec G, Yamamoto H, Perucha E, Sacks SS, Köhl J, Cook HT, Kemper C.; ''C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation.''; PubMedEurope PMCScholia
Lee YT, Jacob J, Michowski W, Nowotny M, Kuznicki J, Chazin WJ.; ''Human Sgt1 binds HSP90 through the CHORD-Sgt1 domain and not the tetratricopeptide repeat domain.''; PubMedEurope PMCScholia
Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J.; ''A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes.''; PubMedEurope PMCScholia
Qu Y, Franchi L, Nunez G, Dubyak GR.; ''Nonclassical IL-1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages.''; PubMedEurope PMCScholia
Shen Z, Huang S, Fang M, Wang X.; ''ENTPD5, an endoplasmic reticulum UDPase, alleviates ER stress induced by protein overloading in AKT-activated cancer cells.''; PubMedEurope PMCScholia
Piippo N, Korhonen E, Hytti M, Skottman H, Kinnunen K, Josifovska N, Petrovski G, Kaarniranta K, Kauppinen A.; ''Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome.''; PubMedEurope PMCScholia
Mulero JJ, Yeung G, Nelken ST, Bright JM, McGowan DW, Ford JE.; ''Biochemical characterization of CD39L4.''; PubMedEurope PMCScholia
Liyanage NP, Fernando MR, Lou MF.; ''Regulation of the bioavailability of thioredoxin in the lens by a specific thioredoxin-binding protein (TBP-2).''; PubMedEurope PMCScholia
Gicquel T, Robert S, Loyer P, Victoni T, Bodin A, Ribault C, Gleonnec F, Couillin I, Boichot E, Lagente V.; ''IL-1β production is dependent on the activation of purinergic receptors and NLRP3 pathway in human macrophages.''; PubMedEurope PMCScholia
Jo EK, Kim JK, Shin DM, Sasakawa C.; ''Molecular mechanisms regulating NLRP3 inflammasome activation.''; PubMedEurope PMCScholia
Kaczmarek E, Koziak K, Sévigny J, Siegel JB, Anrather J, Beaudoin AR, Bach FH, Robson SC.; ''Identification and characterization of CD39/vascular ATP diphosphohydrolase.''; PubMedEurope PMCScholia
Manji GA, Wang L, Geddes BJ, Brown M, Merriam S, Al-Garawi A, Mak S, Lora JM, Briskin M, Jurman M, Cao J, DiStefano PS, Bertin J.; ''PYPAF1, a PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kappa B.''; PubMedEurope PMCScholia
Enjyoji K, Sévigny J, Lin Y, Frenette PS, Christie PD, Esch JS, Imai M, Edelberg JM, Rayburn H, Lech M, Beeler DL, Csizmadia E, Wagner DD, Robson SC, Rosenberg RD.; ''Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation.''; PubMedEurope PMCScholia
Lai Y, Gallo RL.; ''Toll-like receptors in skin infections and inflammatory diseases.''; PubMedEurope PMCScholia
Mizumoto N, Kumamoto T, Robson SC, Sévigny J, Matsue H, Enjyoji K, Takashima A.; ''CD39 is the dominant Langerhans cell-associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness.''; PubMedEurope PMCScholia
Kukulski F, Lévesque SA, Sévigny J.; ''Impact of ectoenzymes on p2 and p1 receptor signaling.''; PubMedEurope PMCScholia
Navas A, Vargas DA, Freudzon M, McMahon-Pratt D, Saravia NG, Gómez MA.; ''Chronicity of dermal leishmaniasis caused by Leishmania panamensis is associated with parasite-mediated induction of chemokine gene expression.''; PubMedEurope PMCScholia
Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Colegio OR, Tephly LA, Carter AB, Rothman PB, Flavell RA, Sutterwala FS.; ''The Nalp3 inflammasome is essential for the development of silicosis.''; PubMedEurope PMCScholia
Kim M, Spelta V, Sim J, North RA, Surprenant A.; ''Differential assembly of rat purinergic P2X7 receptor in immune cells of the brain and periphery.''; PubMedEurope PMCScholia
Garavaglia S, Bruzzone S, Cassani C, Canella L, Allegrone G, Sturla L, Mannino E, Millo E, De Flora A, Rizzi M.; ''The high-resolution crystal structure of periplasmic Haemophilus influenzae NAD nucleotidase reveals a novel enzymatic function of human CD73 related to NAD metabolism.''; PubMedEurope PMCScholia
Mayor A, Martinon F, De Smedt T, Pétrilli V, Tschopp J.; ''A crucial function of SGT1 and HSP90 in inflammasome activity links mammalian and plant innate immune responses.''; PubMedEurope PMCScholia
P2X1 protein readily forms stable trimers and hexamers, suggesting that the intact receptor is a multimer of three or six subunits in heterologous expression systems. However,assembly in native cells may be influenced significantly by associated proteins that are not present in heterologous expression systems.
ROS induce the dissociation of TXNIP from thioredoxin, freeing TXNIP to subsequently bind NLRP3 and bring about activation of the NLRP3 inflammasome (Zhou et al. 2010).
TXNIP interacts with the redox-active domain of thioredoxin (TRX) and is believed to act as an oxidative stress mediator by inhibiting TRX activity or by limiting its bioavailability (Nishiyama et al. 1999, Liyanage et al. 2007).
Thioredoxin-interacting protein (TXNIP) binds NLRP3. Reactive oxygen species (ROS) such as H2O2 increase this interaction, while the ROS inhibitor APDC blocks it (Zhou et al. 2010). This interaction is proposed to activate the NLRP3 inflammasome.
The presence of reactive oxygen species (ROS) leads to the oxidation of thioredoxin and consequent release of TXNIP (Zhou et al. 2010). The source of the ROS is unclear but they are known to be essential for caspase-1 activation (Cruz et al. 2007) and are produced in response to all known NLRP3 activators (Dostert et al. 2008, Zhou et al. 2010). The freed TXNIP binds NLRP3 and is proposed to activate the NLRP3 inflammasome, explaining how ROS can bring about NLRP3 activation.
The NLRP3 inflammasome is activated by a range of stimuli of microbial, endogenous and exogenous origins including several viruses, bacterial pore forming toxins (e.g. Craven et al. 2009), and various irritants that form crystalline or particulate structures (see Cassel et al. 2009). Multiple studies have shown that phagocytosis of particulate elicitors is necessary for activation (e.g. Hornung et al. 2008) but not for the response to ATP, which is mediated by the P2X7 receptor (Kahlenberg & Dubyak, 2004) and appears to involve the pannexin membrane channel (Pellegrin & Suprenenant 2006), which is also involved in the response to nigericin and maitotoxin (Pellegrin & Suprenenant 2007). Direct binding of elicitors to NLRP3 has not been demonstrated and the exact process of activation is unclear, though speculated to involve changes in conformation that make available the NACHT domain for oligomerization (Inohara & Nunez 2001, 2003).
Three overlapping mechanisms are believed to be involved in NLRP3 activation. ATP stimulates the P2X7 ATP-gated ion channel leading to K+ efflux which appears necessary for NLRP3 inflammasome activation (Kahlenberg & Dubyak 2004, Dostert et al. 2008), and is believed to induce formation of pannexin-1 membrane pores. These pores give direct access of NLPR3 agonists to the cytosol. A second mechanism is the endocytosis of crystalline or particulate structures, leading to damaged lysosomes which release their contents (Hornung et al. 2008, Halle et al. 2008). The third element is the generation of reactive oxygen species (ROS) which activate NLRP3, shown to be a critical step for the activation of caspase-1 following ATP stimulation (Cruz et al. 2007). The source of the ROS is unclear.
The complement component 3a receptor (C3AR) binds C3a, a 77-amino acid anaphylatoxin generated after proteolytic cleavage of C3 and C5 in response to complement activation. C3a is involved in a variety of inflammatory responses including chemotaxis and activation of granulocytes, mast cells and macrophages (Peng et al. 200, Klos et al. 2009).
Pro-interleukin-1 beta (pro-IL1B) is the primary substrate of caspase-1. IL1B production and processing is stimulated when pathogen-associated molecular patterns (PAMPs) such as bacterial LPS are detected by cells of the innate immune system, and in response to pro-inflammatory cytokines such as TNF. Detection of PAMPs by Toll receptors leads to rapid IL1 transcription/translation and subsequent processing by caspase-1 in macrophages and monocytes. Processing is triggered by the activation of members of the NLR family and their associated inflammasome complexes. IL1B lacks a signal peptide to direct it to the Golgi for subsequent secretion, so the mode of secretion is uncertain. Once secreted, IL1B binds membrane-bound IL1 receptors, followed by recruitment of the IL1 receptor accessory protein to form a high affinity receptor complex. Ligand induced receptor activation induces the intracellular association of a number of cytosolic adapter proteins triggering intracellular signal transduction. This series of steps facilitates the induction of nuclear factor-kappa B (NFkB) and mitogen-activated protein kinase (MAPK) activity, leading to downstream transcription of additional inflammatory cytokines, including IL1B itself. A calpain-like potease has been reported to be important for the processing of pro- IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology.
Interleukin-1β (IL-1β) lacks signal sequences for compartmentation within the Golgi and classical secretory vesicles, so release of the mature form to extracellular compartments requires nonclassical mechanisms of secretion which are poorly understood (Eder C 2009; Piccioli P & Rubartelli A 2013). Several secretory pathways were proposed involving secretory lysosomes, exosomes, microvesicles, and autophagic vesicles, possibly through a mechanism similar to chaperone-mediated autophagy (CMA) (Andrei C et al. 2004; Ward JR et al. 2010; MacKenzie A et al. 2001; Gudipaty L et al. 2003; Qu Y et al. 2007; Iula L et al. 2018: reviewed by Eder C 2009; Piccioli P & Rubartelli A 2013; Claude-Taupin A et al. 2018). Further, the route of IL-1β secretion was found to be dependent on the type and strength of the inflammatory stimuli (Semino C et al. 2018; Sitia R & Rubartelli A 2018). Thus, in primary human monocytes small trauma or low pathogen load (LPS) activated a pathway involving secretory lysosomes that allows slow release of IL-1β, followed by apoptotic cell death that switches off the inflammatory response (Semino C et al. 2018). Differently, a stronger stimulus (LRZ) resulted in gasdermin D (GSDMD) cleavage with generation of the N-terminal domain that assembles in N-rings with formation of pores through which IL-1β can be externalized: this pathway of secretion is followed by pyroptosis, with membrane ruptures through which DAMPs can leave cells, further amplifying the inflammatory response (Semino C et al. 2018).
NLRP3 interacts with ASC (Manji et al. 2003) via their PYD domains (Dowds et al. 2004). NLRP3 oligomerization leads to PYD domain clustering which is believed to facilitate the interaction of NLRP3 with the PYD domain of ASC (Schroder & Tschopp, 2010).
Procaspase-1 is recruited via a CARD-CARD interaction with ASC. This creates procaspase-1 clustering which is believed to stimulate procaspase-1 autocleavage, generating the p10/p20 fragments that assemble into the active capsase-1 tetramer (Schroder & Tschopp, 2010).
Genetic studies in plants suggest a role for SGT1-HSP90 as co-chaperones of plant resistance (R) proteins, serving to maintain them in an inactive but signaling-competent state. R-protein activation is beleived to lead to dissociation of the SGT1-HSP90 complex. SGT1 and HSP90 are highly conserved, while R proteins are structurally related to mammalian NLRs.
Human SGT1 and HSP90 were found to bind NLRP3 (Mayor et al. 2007). Knockdown of human SGT1 by small interfering RNA or chemical inhibition of HSP90 by geldanamycin abrogated NLRP3 inflammasome activity in human monocytic cell line THP-1 (Mayor et al. 2007). Similarly, NLRP3 inflammasome activation was abrogated in geldanamycin-treated human retinal pigment epithelial (RPE) cells (Piippo N et al. 2018). These data indicate that SGT1 and HSP90 are involved in regulation of NLRP3 inflammasome signaling (Mayor et al. 2007; Piippo N et al. 2018).
The ubiquitin ligase–associated protein SGT1 (SUGT1) has two putative HSP90 binding domains, a tetratricopeptide repeat and a p23-like CHORD and Sgt1 (CS) domain. The CS domain of human SGT1 physically interacts with HSP90. SGT1 and related proteins are believed to recruit heat shock proteins to multiprotein assemblies (Lee et al. 2004).
Trimeric pyrin interacts with ASC through its Pyrin domains, leading to oligomerization of ASC. This interaction interferes with the ability of NLRP3 (Cyropyrin) to associate with ASC and thus inhibits inflammasome activation (Chae et al. 2003).
Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) is a pyrin-binding protein, involved in regulation of the actin cytoskeleton (Li et al. 1998) and suggested as a regulator of inflammasome activation (Khare et al. 2010). A naturally occurring mutation of PSTPIP1 where Y344 is replaced by F blocks tyrosine phosphorylation and reduces pyrin binding. Mutations of PSTPIP1 that increase pyrin binding are associated with the inflammatory syndrome pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA). Expression of PSTPIP1 with these mutations in THP-11 cells resulted in substantially increased caspase-1 activation and IL-1beta secretion. PSTPIP1 binding to pyrin is believed to promote the unmasking of its PYD domain and enhance interactions with ASC, facilitating ASC oligomerization and caspase-1 recruitment (Yu et al. 2007).
NTPDase1 (CD39) is a plasma membrane-bound ectonucleotidase encoded by the ENTPD1 gene that hydrolyzes extracellular NTPs to NMPs, via corresponding NDP intermediates (Lemmens et al. 2000, Kukulski et al. 2005). NTPDase1 is expressed on endothelial cells, smooth muscle cells and most leukocytes. The vascular endothelial NTPDase1 regulates platelet aggregation and thrombosis (Kaczmarek et al. 1996, Enjoyji et al. 1999). In mice, NTPDase1 is expressed at the surface of epidermal dendritic cells (Langerhans cells) and is involved in regulation of immune response to skin irritants (Mizumoto et al. 2002). NTPDase1 expressed in vascular smooth muscle cells regulates vasomotion (Kauffenstein et al. 2010, reviewed by Kukulski et al. 2011). In regulatory T lymphocytes (Tregs) and other leukocytes NTPDase1 regulates inflammatory processes (Deaglio et al. 2007).
NTPDase5 (CD39L4), encoded by the ENTPD5 gene, is an E-NTPDase family member that is secreted to the extracellular space where it hydrolyzes nucleoside diphosphates UDP, GDP, CDP and ADP (listed in the order of preference) to nucleoside monophosphates UMP, GMP, CMP and AMP, respectively. In vitro, NTPDase5 can hydrolyze nucleoside triphosphates GTP, CTP, UTP and ATP to corresponding nucleoside diphosphates but with very low efficiency. NTPDase5 requires Ca2+ or Mg2+ for catalytic activity (Mulero et al. 1999). NTPDase5 is most catalytically active as a monomer, although it can also form disulfide-linked dimers (Mulero et al. 2000).
NTPDase5 may function in the endoplasmic reticulum (ER), where its UDPase activity could contribute to protein glycosylation and folding. NTPDase5 may alleviate ER stress induced by protein overload caused by oncogenic PI3K/AKT signaling in cancer cells. NTPDase5 is over-expressed in tumors with activated AKT and is known as the PCPH oncogene. The underlying mechanism of NTPDase5 over-expression may be AKT-mediated inhibition of FOXO proteins, which are probable transcriptional repressors of the ENTPD5 gene (Fang et al. 2010, Shen et al. 2011).
5'-nucleotidase (NT5E, CD73) is able to hydrolyse extracellular nucleotides into membrane permeable nucleosides. It displays a broad specificity, acting on mono- or di-nucleotide nicotinamides and different adenosine phosphates, with maximal activity on 5'-adenosine monophosphate. Human NT5E can hydrolyse both NAD+ and NMN, suggesting a role in NAD metabolism (Garavaglia et al. 2012). NT5E is a glycolipid-anchored plasma membrane enzyme (Misumi et al. 1990) that is active in dimeric form and requires one zinc ion per subunit (Zimmermann 1992).
Two signals are required for NLRP3 inflammasome activation. Signal 1, also known as the priming signal, is mediated by microbial ligands recognised by TLRs or cytokines such as TNF-α which activate the NF-κB pathway, leading to upregulation of pro-IL-1β and NLRP3 protein levels (Bauernfeind et al. 2009, Jo et al. 2016).
P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to the binding of extracellular adenosine triphosphate (ATP) (Gicquel et al. 2015). All members of the family are thought to be functionally trimeric.
At low to intermediate concentrations of extracellular ATP, P2X4 and P2X7 probably function as heterotrimeric, reversible ATP-gated, non-desensitizing cation channels (Markwardt 2007).
It has been shown that anaphylatoxin C3a binding to its receptor C3AR1 indirectly activates the proinflammatory cytokine IL1β (Laudisi, 2013 and Asgari, 2013). Asgari et al. suggest a mechanism; after the binding of C3a to C3AR1, ATP release is promoted from the cytosol to the extracellular space through an unknown channel. From here, ATP binding to P2X purinoceptors activates the inflammasome that results in the production of IL1β (Asgari 2013).
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DataNodes
N-terminal
propeptideselicitors:NLRP3
oligomer:ASC:Procaspase-1elicitors:NLRP3
oligomer:ASCelicitors:NLRP3
oligomerAnnotated Interactions
N-terminal
propeptideselicitors:NLRP3
oligomer:ASC:Procaspase-1elicitors:NLRP3
oligomer:ASCelicitors:NLRP3
oligomer:ASCelicitors:NLRP3
oligomerThree overlapping mechanisms are believed to be involved in NLRP3 activation. ATP stimulates the P2X7 ATP-gated ion channel leading to K+ efflux which appears necessary for NLRP3 inflammasome activation (Kahlenberg & Dubyak 2004, Dostert et al. 2008), and is believed to induce formation of pannexin-1 membrane pores. These pores give direct access of NLPR3 agonists to the cytosol. A second mechanism is the endocytosis of crystalline or particulate structures, leading to damaged lysosomes which release their contents (Hornung et al. 2008, Halle et al. 2008). The third element is the generation of reactive oxygen species (ROS) which activate NLRP3, shown to be a critical step for the activation of caspase-1 following ATP stimulation (Cruz et al. 2007). The source of the ROS is unclear.
Genetic studies in plants suggest a role for SGT1-HSP90 as co-chaperones of plant resistance (R) proteins, serving to maintain them in an inactive but signaling-competent state. R-protein activation is beleived to lead to dissociation of the SGT1-HSP90 complex. SGT1 and HSP90 are highly conserved, while R proteins are structurally related to mammalian NLRs.
Human SGT1 and HSP90 were found to bind NLRP3 (Mayor et al. 2007). Knockdown of human SGT1 by small interfering RNA or chemical inhibition of HSP90 by geldanamycin abrogated NLRP3 inflammasome activity in human monocytic cell line THP-1 (Mayor et al. 2007). Similarly, NLRP3 inflammasome activation was abrogated in geldanamycin-treated human retinal pigment epithelial (RPE) cells (Piippo N et al. 2018). These data indicate that SGT1 and HSP90 are involved in regulation of NLRP3 inflammasome signaling (Mayor et al. 2007; Piippo N et al. 2018).
NTPDase5 may function in the endoplasmic reticulum (ER), where its UDPase activity could contribute to protein glycosylation and folding. NTPDase5 may alleviate ER stress induced by protein overload caused by oncogenic PI3K/AKT signaling in cancer cells. NTPDase5 is over-expressed in tumors with activated AKT and is known as the PCPH oncogene. The underlying mechanism of NTPDase5 over-expression may be AKT-mediated inhibition of FOXO proteins, which are probable transcriptional repressors of the ENTPD5 gene (Fang et al. 2010, Shen et al. 2011).