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NOD-like receptor
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<h2 id="structure">Structure</h2> <p>NLRs contain 3 domains – central <a href="/facts/NACHT_domain/WD50RAfm">NACHT</a> (NOD or NBD – nucleotide-binding domain) domain, which is common to all NLRs, most of NLRs have also C-terminal <a href="/facts/Leucine-rich_repeat/MG6yCfDQ">leucine-rich repeat</a> (LRR) and variable N-terminal interaction domain. NACHT domain mediates ATP-dependent self-oligomerization and LRR senses the presence of ligand. N-terminal domain is responsible for homotypic protein-protein interaction and it can consist of <a href="/facts/CARD_domain/ySJupuCo">caspase recruitment domain</a> (CARD), <a href="/facts/Pyrin_domain/zAa8bF9j">pyrin domain</a> (PYD), acidic transactivating domain or <a href="/facts/Inhibitor_of_apoptosis_domain/02s2PQFg">baculovirus inhibitor repeats</a> (BIRs).<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <h2 id="nomenclature-and-system">Nomenclature and system</h2> <p>Names as CATERPILLER, NOD, NALP, PAN, NACHT, PYPAF were used to describe the NLRs family. The nomenclature was unified by the <a href="/facts/HUGO_Gene_Nomenclature_Committee/c26pY9tE">HUGO Gene Nomenclature Committee</a> in 2008. The family was characterized as NLRs to provide description of the families features – NLR means nucleotide-binding domain and leucine-rich repeat containing gene family.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p><p>This system divides NLRs into 4 subfamilies based on the type of N-terminal domain: </p> <ul><li>NLRA (A for acidic transactivating domain): <a href="/facts/CIITA/Ecbb2B91">CIITA</a></li> <li>NLRB (B for <a href="/facts/Inhibitor_of_apoptosis_domain/02s2PQFg">BIRs</a>): <a href="/facts/NAIP_(gene)/GaPsRyre">NAIP</a></li> <li>NLRC (C for <a href="/facts/CARD_domain/ySJupuCo">CARD</a>): <a href="/facts/NOD1/zAzVCWaf">NOD1</a>, <a href="/facts/NOD2/zhx0pnLD">NOD2</a>, <a href="/facts/NLRC3/yRyJpPHx">NLRC3</a>, <a href="/facts/NLRC4/18VPtglo">NLRC4</a>, <a href="/facts/NLRC5/Xc7E7oCU">NLRC5</a></li> <li>NLRP (P for <a href="/facts/Pyrin_domain/zAa8bF9j">PYD</a>): <a href="/facts/NLRP1/4Vvn7IGe">NLRP1</a>, <a href="/facts/NLRP2/Itko4s3L">NLRP2</a>, <a href="/facts/NLRP3/6z5AIMjU">NLRP3</a>, <a href="/facts/NLRP4/vDYxs37Y">NLRP4</a>, <a href="/facts/NLRP5/wnQxHmIW">NLRP5</a>, <a href="/facts/NLRP6/u9YHjGSs">NLRP6</a>, <a href="/facts/NLRP7/U6qJPWfQ">NLRP7</a>, <a href="/facts/NLRP8/Nu1D133t">NLRP8</a>, <a href="/facts/NLRP9/87NatPu4">NLRP9</a>, <a href="/facts/NLRP10/WkbYKRJy">NLRP10</a>, <a href="/facts/NLRP11/5WUDso16">NLRP11</a>, <a href="/facts/NLRP12/ornNPhou">NLRP12</a>, <a href="/facts/NLRP13/KTr6d3gE">NLRP13</a>, <a href="/facts/NLRP14/kms1Wjps">NLRP14</a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a></li></ul> <p>There is also an additional subfamily NLRX which doesn't have significant homology to any N-terminal domain. A member of this subfamily is <a href="/facts/NLRX1/SVjdRLvd">NLRX1</a>.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p><p>On the other hand, NLRs can be divided into 3 subfamilies with regard to their phylogenetic relationships: </p> <ul><li>NODs: <a href="/facts/NOD1/zAzVCWaf">NOD1</a>, <a href="/facts/NOD2/zhx0pnLD">NOD2</a>, <a href="/facts/NLRC3/yRyJpPHx">NOD3</a> (<a href="/facts/NLRC3/yRyJpPHx">NLRC3</a>), <a href="/facts/NLRC5/Xc7E7oCU">NOD4</a> (<a href="/facts/NLRC5/Xc7E7oCU">NLRC5</a>), <a href="/facts/NLRX1/SVjdRLvd">NOD5</a> (<a href="/facts/NLRX1/SVjdRLvd">NLRX1</a>), <a href="/facts/CIITA/Ecbb2B91">CIITA</a></li> <li>NLRPs (also called NALPs): <a href="/facts/NLRP1/4Vvn7IGe">NLRP1</a>, <a href="/facts/NLRP2/Itko4s3L">NLRP2</a>, <a href="/facts/NLRP3/6z5AIMjU">NLRP3</a>, <a href="/facts/NLRP4/vDYxs37Y">NLRP4</a>, <a href="/facts/NLRP5/wnQxHmIW">NLRP5</a>, <a href="/facts/NLRP6/u9YHjGSs">NLRP6</a>, <a href="/facts/NLRP7/U6qJPWfQ">NLRP7</a>, <a href="/facts/NLRP8/Nu1D133t">NLRP8</a>, <a href="/facts/NLRP9/87NatPu4">NLRP9</a>, <a href="/facts/NLRP10/WkbYKRJy">NLRP10</a>, <a href="/facts/NLRP11/5WUDso16">NLRP11</a>, <a href="/facts/NLRP12/ornNPhou">NLRP12</a>, <a href="/facts/NLRP13/KTr6d3gE">NLRP13</a>, <a href="/facts/NLRP14/kms1Wjps">NLRP14</a></li> <li>IPAF: <a href="/facts/NLRC4/18VPtglo">IPAF</a> (<a href="/facts/NLRC4/18VPtglo">NLRC4</a>), <a href="/facts/NAIP_(gene)/GaPsRyre">NAIP</a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a></li></ul> <h2 id="subfamily-nods">Subfamily NODs</h2> <p>NODs subfamily consists of NOD1, NOD2, NOD3, NOD4 with CARD domain, CIITA containing acidic transactivator domain and NOD5 without any N-terminal domain.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> <a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h3>Signalling</h3> <p>The well-described receptors are NOD1 and NOD2. The recognition of their ligands recruits oligomerization of NACHT domain and CARD-CARD interaction with CARD-containing serine-threonin <a href="/facts/RIPK2/T9Port4U">kinase RIP2</a> which leads to activation of RIP2.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> RIP2 mediates the recruitment of kinase TAK1 which phosphorylates and activates <a href="/facts/I%25CE%25BAB_kinase/kD0lhSDA">IκB kinase</a>. The activation of IκB kinase results in the phosphorylation of inhibitor IκB which releases <a href="/facts/NF-%25CE%25BAB/qcpt5vuQ">NF-κB</a> and its nuclear translocation. NF-κB then activates expression of <a href="/facts/Inflammatory_cytokine/eKSJ4Qw8">inflammatory cytokines</a>.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> Mutations in NOD2 are associated with <a href="/facts/Crohn%2527s_disease/zm55cBtd">Crohn's disease</a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> or <a href="/facts/Blau_syndrome/M0YswUzd">Blau syndrome</a>.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p> <h3>Ligands</h3> <p>NOD1 and NOD2 recognize <a href="/facts/Peptidoglycan/lflRRUNw">peptidoglycan</a> motifs from bacterial cell which consists of <a href="/facts/N-acetylglucosamine/bp9qxgNS">N-acetylglucosamine</a> and <a href="/facts/N-acetylmuramic_acid/uIDxFy1S">N-acetylmuramic acid</a>. These sugar chains are cross-linked by peptide chains that can be sensed by NODs. NOD1 recognizes a molecule called <a href="/facts/Diaminopimelic_acid/vv3BoWGv">meso-diaminopimelic acid</a> (meso-DAP) mostly found in <a href="/facts/Gram-negative_bacteria/S1PbVtp4">Gram-negative bacteria</a> (for example <i><a href="/facts/Helicobacter_pylori/9q4H68LP">Helicobacter pylori</a></i>, <i><a href="/facts/Pseudomonas_aeruginosa/HBhyIxAn">Pseudomonas aeruginosa</a></i>). NOD2 proteins can sense intracellular <a href="/facts/Muramyl_dipeptide/e767jduN">muramyl dipeptide</a> (MDP), typical for bacteria such as <i><a href="/facts/Streptococcus_pneumoniae/B5XxK27j">Streptococcus pneumoniae</a></i> or <i><a href="/facts/Mycobacterium_tuberculosis/cbRjnhIQ">Mycobacterium tuberculosis</a></i>.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p> <h2 id="subfamilies-nlrps-and-ipaf">Subfamilies NLRPs and IPAF</h2> <p>NLRPs subfamily contains NLRP1-NLRP14 that are characterized by the presence of PYD domain. IPAF subfamily has two members – IPAF with CARD domain and NAIP with BIR domain.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p> <h3>Signalization</h3> <p>NLRPs and IPAF subfamilies are involved in the formation of the <a href="/facts/Inflammasome/pUt8Fgpr">inflammasome</a>. The best characterized inflammasome is <a href="/facts/NALP3/6z5AIMjU">NLRP3</a>, the activation through <a href="/facts/PAMPs/jLrjQv7T">PAMPs</a> or <a href="/facts/DAMPs/6nTcgFu1">DAMPs</a> leads to the oligomerization.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> The pyrin domain of NLRs binds to an adaptor protein <a href="/facts/PYCARD/036jA6Jt">ASC (PYCARD)</a> via PYD-PYD interaction. ASC contains PYD and CARD domain and links the NLRs to inactive form of <a href="/facts/Caspase_1/SUUwJoo1">caspase 1</a> through the CARD domain.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> All these protein-protein interaction form a complex called the inflammasome. The aggregation of the pro-caspase-1 causes the autocleavage and formation of an active enzyme. Caspase-1 is important for the proteolytic processing of the pro-inflammatory cytokines <a href="/facts/Interleukin_1_family/dSToCWMd">IL-1β</a> and <a href="/facts/Interleukin_18/WIxCeLEk">IL-18</a>.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a><a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> NLRP3 mutations are responsible for the autoinflammatory disease <a href="/facts/Familial_cold_urticaria/dbbHLcYP">familial cold autoinflammatory syndrome</a> or <a href="/facts/Muckle%25E2%2580%2593Wells_syndrome/GPuk6QxE">Muckle–Wells syndrome</a>.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a><a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p> <h3>Ligands</h3> <p>There are three well-characterized inflammasomes – NLRP1, NLRP3 and IPAF. The formation of <a href="/facts/NLRP3_inflammasome/pUt8Fgpr">NLRP3 inflammasome</a> can be activated by <a href="/facts/PAMPs/jLrjQv7T">PAMPs</a> such as microbial toxins (for example alpha-toxin of <i><a href="/facts/Staphylococcus_aureus/9yDVBMsc">Staphylococcus aureus</a></i>) or whole pathogens, for instance <i><a href="/facts/Candida_albicans/7o27aEFS">Candida albicans</a></i>, <i><a href="/facts/Saccharomyces_cerevisiae/sX9MGFrz">Saccharomyces cerevisiae</a></i>, <a href="/facts/Sendai_virus/sP7IkwR9">Sendai virus</a>, <a href="/facts/Influenza/nWuFzh6L">Influenza</a>. NLRP3 recognize also <a href="/facts/DAMPs/6nTcgFu1">DAMPs</a> which indicate stress in the cell. The danger molecule can be extracellular ATP, extracellular glucose, <a href="/facts/Monosodium_urate_crystals/gPMSfLcT">monosodium urate (MSU) crystals</a>, calcium pyrophosphate dihydrate (CPPD), <a href="/facts/Alum/ULAn0XRB">alum</a>, <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a> or environmental irritants – <a href="/facts/Silicon_dioxide/A3WILp6J">silica</a>, <a href="/facts/Asbestos/dEnjQyee">asbestos</a>, <a href="/facts/Ultraviolet/kncBUqn5">UV</a> irradiation and skin irritants. The presence of these molecules causes a production of <a href="/facts/Reactive_oxygen_species/GpwSRugH">ROS</a> and K+ efflux. NLRP1 recognizes lethal toxin from <i><a href="/facts/Bacillus_anthracis/suoM7vhx">Bacillus anthracis</a></i> and <a href="/facts/Muramyl_dipeptide/e767jduN">muramyl dipeptide</a>. IPAF senses <a href="/facts/Flagellin/d7lSufnD">flagellin</a> from <i><a href="/facts/Salmonella_typhimurium/aj5Ax3uG">Salmonella typhimurium</a></i>, <i><a href="/facts/Pseudomonas_aeruginosa/HBhyIxAn">Pseudomonas aeruginosa</a></i>, <i><a href="/facts/Listeria_monocytogenes/Cq1a7zqe">Listeria monocytogenes</a></i>.<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a><a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a><a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Toll-like_receptor/hj4qIWP8">Toll-like receptor</a></li> <li><a href="/facts/Inflammasome/pUt8Fgpr">Inflammasome</a></li> <li><a href="/facts/RIG-I-like_receptor/BzYsTMVd">RIG-I-like receptor</a></li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://www.ebi.ac.uk/interpro/beta/entry/panther/PTHR14074/">PTHR14074</a> (<a href="https://www.ebi.ac.uk/interpro/beta/entry/panther/PTHR24106/protein/UniProt/taxonomy/uniprot/9606/">filter for human</a>)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Mahla, Ranjeet (2013). "Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology". Front Immunol. 4: 248. doi:10.3389/fimmu.2013.00248. PMC 3759294. PMID 24032031. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759294" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759294</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Mahla RS, Reddy MC, Prasad DV, Kumar H (September 2013). "Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology". Frontiers in Immunology. 4: 248. doi:10.3389/fimmu.2013.00248. PMC 3759294. PMID 24032031. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759294" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759294</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Franchi L, Warner N, Viani K, Nuñez G (2009). "Function of Nod-like receptors in microbial recognition and host defense". Immunol Rev. 227 (1): 106–28. doi:10.1111/j.1600-065X.2008.00734.x. PMC 2679989. PMID 19120480. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679989" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679989</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G (2001). "Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB". J Biol Chem. 276 (7): 4812–8. doi:10.1074/jbc.M008072200. PMID 11087742. <a href="https://doi.org/10.1074%2Fjbc.M008072200" target="_blank">https://doi.org/10.1074%2Fjbc.M008072200</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Inohara N, Ogura Y, Chen FF, Muto A, Nuñez G (2001). "Human Nod1 confers responsiveness to bacterial lipopolysaccharides". J Biol Chem. 276 (4): 2551–4. doi:10.1074/jbc.M009728200. PMID 11058605. <a href="https://doi.org/10.1074%2Fjbc.M009728200" target="_blank">https://doi.org/10.1074%2Fjbc.M009728200</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Inohara N, Ogura Y, Chen FF, Muto A, Nuñez G (2001). "Human Nod1 confers responsiveness to bacterial lipopolysaccharides". J Biol Chem. 276 (4): 2551–4. doi:10.1074/jbc.M009728200. PMID 11058605. <a href="https://doi.org/10.1074%2Fjbc.M009728200" target="_blank">https://doi.org/10.1074%2Fjbc.M009728200</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Franchi L, Warner N, Viani K, Nuñez G (2009). "Function of Nod-like receptors in microbial recognition and host defense". Immunol Rev. 227 (1): 106–28. doi:10.1111/j.1600-065X.2008.00734.x. PMC 2679989. 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PMID 18219313. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2267388" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2267388</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Schroder K, Tschopp J (2010). "The inflammasomes". Cell. 140 (6): 821–32. doi:10.1016/j.cell.2010.01.040. PMID 20303873. <a href="https://doi.org/10.1016%2Fj.cell.2010.01.040" target="_blank">https://doi.org/10.1016%2Fj.cell.2010.01.040</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Schroder K, Tschopp J (2010). "The inflammasomes". Cell. 140 (6): 821–32. doi:10.1016/j.cell.2010.01.040. PMID 20303873. <a href="https://doi.org/10.1016%2Fj.cell.2010.01.040" target="_blank">https://doi.org/10.1016%2Fj.cell.2010.01.040</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Chen G, Shaw MH, Kim YG, Nuñez G (2009). "NOD-like receptors: role in innate immunity and inflammatory disease". Annu Rev Pathol. 4: 365–98. doi:10.1146/annurev.pathol.4.110807.092239. PMID 18928408. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M, Body-Malapel M, et al. (2007). "RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs". J Immunol. 178 (4): 2380–6. doi:10.4049/jimmunol.178.4.2380. PMID 17277144. <a href="https://doi.org/10.4049%2Fjimmunol.178.4.2380" target="_blank">https://doi.org/10.4049%2Fjimmunol.178.4.2380</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Núñez G, et al. (2008). "A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation". EMBO J. 27 (2): 373–83. doi:10.1038/sj.emboj.7601962. PMC 2234345. 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