NLRP1

{{Short description|Human protein-coding gene}} {{cs1 config|name-list-style=vanc|display-authors=3}} {{Infobox_gene}} '''NLRP1''' encodes '''NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1''' in humans.<ref name="pmid8781126">{{cite journal | vauthors = Thorpe KL, Abdulla S, Kaufman J, Trowsdale J, Beck S | title = Phylogeny and structure of the RING3 gene | journal = Immunogenetics | volume = 44 | issue = 5 | pages = 391–6 | date = Oct 1996 | pmid = 8781126 | doi = 10.1007/BF02602785 | s2cid = 44613743 }}</ref><ref name="pmid12563287">{{cite journal | vauthors = Tschopp J, Martinon F, Burns K | title = NALPs: a novel protein family involved in inflammation | journal = Nature Reviews. Molecular Cell Biology | volume = 4 | issue = 2 | pages = 95–104 | date = February 2003 | pmid = 12563287 | doi = 10.1038/nrm1019 | bibcode = 2003NRMCB...4...95T | s2cid = 31417018 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NLRP1 NLR family, pyrin domain containing 1| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=22861}}</ref> NLRP1 was the first protein shown to form an inflammasome.<ref name=":0">{{cite journal | vauthors = Chavarría-Smith J, Mitchell PS, Ho AM, Daugherty MD, Vance RE | title = Functional and Evolutionary Analyses Identify Proteolysis as a General Mechanism for NLRP1 Inflammasome Activation | journal = PLOS Pathogens | volume = 12 | issue = 12 | article-number = e1006052 | date = December 2016 | pmid = 27926929 | pmc = 5142783 | doi = 10.1371/journal.ppat.1006052 | doi-access = free }} 50px Material was copied from this source, which is available under a [https://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International License].</ref> NLRP1 is expressed by a variety of cell types, which are predominantly epithelial or hematopoietic. The expression is also seen within glandular epithelial structures including the lining of the small intestine, stomach, airway epithelia and in hairless or glabrous skin.<ref name=":1">{{cite journal | vauthors = Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, van Bruggen R, Tschopp J | title = Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response | journal = The Journal of Histochemistry and Cytochemistry | volume = 55 | issue = 5 | pages = 443–52 | date = May 2007 | pmid = 17164409 | doi = 10.1369/jhc.6A7101.2006 | doi-access = free }}</ref> NLRP1 polymorphisms are associated with skin extra-intestinal manifestations in CD.<ref name=":1" /> Its highest expression was detected in human skin, in psoriasis and in vitiligo. Polymorphisms of NLRP1 were found in lupus erythematosus and diabetes type 1.<ref>{{cite journal | vauthors = Grandemange S, Sanchez E, Louis-Plence P, Tran Mau-Them F, Bessis D, Coubes C, Frouin E, Seyger M, Girard M, Puechberty J, Costes V, Rodière M, Carbasse A, Jeziorski E, Portales P, Sarrabay G, Mondain M, Jorgensen C, Apparailly F, Hoppenreijs E, Touitou I, Geneviève D | title = NLRP1-associated autoinflammation with arthritis and dyskeratosis) | journal = Annals of the Rheumatic Diseases | volume = 76 | issue = 7 | pages = 1191–1198 | date = July 2017 | pmid = 27965258 | doi = 10.1136/annrheumdis-2016-210021 | s2cid = 206852426 }}</ref> Variants of mouse NLRP1 were found to be activated upon N-terminal cleavage by the protease in anthrax lethal factor.<ref name=":0" />

== Function ==

This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. The NLRP1 protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce pyroptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined.<ref name="entrez"/>

== Mechanism of activation == NLRP1 activates an antibacterial or antiviral immune response. Antibacterial immune response compensates for the loss of the MAP kinase response. Humans produce NLRP1, but human NLRP1 is not activated by lethal factor.<ref name=":0" /> NLRP1 could be activated by proteolytic cleavage, resulting in the removal of an auto-inhibitory PYD and release of the CARD domain, responsible for the recruitment and activation of pro-caspase-1 in the active form of caspase-1.<ref name=":0" /> Human NLRP1 activation can be elicited by several means including enteroviral 3C proteases.<ref>{{cite journal | vauthors = Robinson KS, Teo DE, Tan KS, Toh GA, Ong HH, Lim CK, Lay K, Au BV, Lew TS, Chu JJ, Chow VT, Wang Y, Zhong FL, Reversade B | title = Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia | journal = Science | volume = 370 | issue = 6521 | date = December 2020 | article-number = eaay2002 | pmid = 33093214 | doi = 10.1126/science.aay2002 | s2cid = 225052810 }}</ref> Its function in immunity is just beginning to be understood.<ref name=":0" />

== Interactions ==

NLRP1 has been shown to interact with caspase 9<ref name=pmid11113115>{{cite journal | vauthors = Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed JC | title = A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis | journal = The Journal of Biological Chemistry | volume = 276 | issue = 12 | pages = 9239–45 | date = March 2001 | pmid = 11113115 | doi = 10.1074/jbc.M006309200 | doi-access = free }}</ref><ref name=pmid11076957>{{cite journal | vauthors = Hlaing T, Guo RF, Dilley KA, Loussia JM, Morrish TA, Shi MM, Vincenz C, Ward PA | title = Molecular cloning and characterization of DEFCAP-L and -S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins | journal = The Journal of Biological Chemistry | volume = 276 | issue = 12 | pages = 9230–8 | date = March 2001 | pmid = 11076957 | doi = 10.1074/jbc.M009853200 | doi-access = free}}</ref> and APAF1.<ref name="pmid11113115" /> Via its FIIND domain, NLRP1 interacts directly with DPP9 and DPP8 which are needed to prevent NLRP1 activation.<ref>{{cite journal | vauthors = Zhong FL, Robinson K, Teo DE, Tan KY, Lim C, Harapas CR, Yu CH, Xie WH, Sobota RM, Au VB, Hopkins R, D'Osualdo A, Reed JC, Connolly JE, Masters SL, Reversade B | title = Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding | journal = The Journal of Biological Chemistry | volume = 293 | issue = 49 | pages = 18864–18878 | date = December 2018 | pmid = 30291141 | doi = 10.1074/jbc.RA118.004350 | pmc = 6295727 | doi-access = free }}</ref>

Loss of DPP9 in humans and mice, results in NLRP1 activation.<ref>{{Cite journal |vauthors=Harapas CR, Robinson KS, Lay K, Wong J, Moreno Traspas R, Nabavizadeh N, Raas-Rothschild A, Boisson B, Drutman SB, Laohamonthonkul P, Bonner D |title=DPP9 deficiency: An inflammasomopathy that can be rescued by lowering NLRP1/IL-1 signaling |journal=Science Immunology |date=2022 |volume=7 |issue=75 |article-number=eabi4611 |doi=10.1126/sciimmunol.abi4611 |pmid=36112693 |pmc=9844213 |medrxiv=10.1101/2021.01.31.21250067}}</ref>

== Variants of NLRP1 in human == Several Mendelian diseases caused by NLRP1 germline mutations have been described.<ref name="pmid27662089">{{cite journal | vauthors = Zhong FL, Mamaï O, Sborgi L, Boussofara L, Hopkins R, Robinson K, Szeverényi I, Takeichi T, Balaji R, Lau A, Tye H, Roy K, Bonnard C, Ahl PJ, Jones LA, Baker PJ, Lacina L, Otsuka A, Fournie PR, Malecaze F, Lane EB, Akiyama M, Kabashima K, Connolly JE, Masters SL, Soler VJ, Omar SS, McGrath JA, Nedelcu R, Gribaa M, Denguezli M, Saad A, Hiller S, Reversade B| title = Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation | journal = Cell | volume = 167 | issue = 1 | pages = 187–202.e17 | date = September 2016 | pmid = 27662089 | doi = 10.1016/j.cell.2016.09.001 | doi-access = free }}</ref> These include Multiple Self-healing Palmoplantar Carcinoma, familial Nikam's disease and Autoinflammation with Arthritis and Dyskeratosis. Mutations in NLRP1, whether dominant or recessive, tend to be gain-of-function alleles that trigger inflammasome signaling with IL1B and IL18 release.

== Variants of NLRP1 in mice == Mice have three paralogs of the ''Nlrp1'' gene (''Nlrp1a, b, c''). ''Nlrp1c'' is a pseudogene.<ref>{{cite journal | vauthors = Sastalla I, Crown D, Masters SL, McKenzie A, Leppla SH, Moayeri M | title = Transcriptional analysis of the three Nlrp1 paralogs in mice | journal = BMC Genomics | volume = 14 | issue = 1 | page = 188 | date = March 2013 | pmid = 23506131 | pmc = 3641005 | doi = 10.1186/1471-2164-14-188 | doi-access = free }}</ref> Mouse NLRP1B is not activated by a receptor-ligand type mechanism. NLRP1B variants from certain inbred mouse strains, BALB/c and 129, can be activated by the lethal factor (LF) protease. The lethal factor protease is produced and secreted by ''Bacillus anthracis'', the agent of anthrax.<ref>{{cite journal | vauthors = Boyden ED, Dietrich WF | title = Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin | journal = Nature Genetics | volume = 38 | issue = 2 | pages = 240–4 | date = February 2006 | pmid = 16429160 | doi = 10.1038/ng1724 | s2cid = 23316987 }}</ref> Together with protective antigen (PA), LF forms a bipartite toxin, Lethal Toxin. The role of PA is to form a translocation channel that delivers LF into the host cell cytosol, where LF play roles in immune response by cleaving and inactivating MAP kinases.<ref>{{cite journal | vauthors = Turk BE | title = Manipulation of host signalling pathways by anthrax toxins | journal = The Biochemical Journal | volume = 402 | issue = 3 | pages = 405–17 | date = March 2007 | pmid = 17313374 | doi = 10.1042/BJ20061891 }}</ref><ref>{{cite journal | vauthors = Moayeri M, Leppla SH | title = Cellular and systemic effects of anthrax lethal toxin and edema toxin | journal = Molecular Aspects of Medicine | volume = 30 | issue = 6 | pages = 439–55 | date = December 2009 | pmid = 19638283 | pmc = 2784088 | doi = 10.1016/j.mam.2009.07.003 }}</ref> LF also directly cleaves NLRP1B proximal to its N-terminus, it is necessary and sufficient for NLRP1B inflammasome formation and CASP1 activation.<ref>{{cite journal | vauthors = Chavarría-Smith J, Vance RE | title = Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor | journal = PLOS Pathogens | volume = 9 | issue = 6 | article-number = e1003452 | date = 2013 | pmid = 23818853 | pmc = 3688554 | doi = 10.1371/journal.ppat.1003452 | doi-access = free }}</ref> Activation of NLRP1B-dependent inflammasome responses appears in host defense with mechanism like IL-1β and neutrophils.<ref>{{cite journal | vauthors = Terra JK, Cote CK, France B, Jenkins AL, Bozue JA, Welkos SL, LeVine SM, Bradley KA | title = Cutting edge: resistance to Bacillus anthracis infection mediated by a lethal toxin sensitive allele of Nalp1b/Nlrp1b | journal = Journal of Immunology | volume = 184 | issue = 1 | pages = 17–20 | date = January 2010 | pmid = 19949100 | pmc = 2811128 | doi = 10.4049/jimmunol.0903114 }}</ref><ref>{{cite journal | vauthors = Moayeri M, Crown D, Newman ZL, Okugawa S, Eckhaus M, Cataisson C, Liu S, Sastalla I, Leppla SH | title = Inflammasome sensor Nlrp1b-dependent resistance to anthrax is mediated by caspase-1, IL-1 signaling and neutrophil recruitment | journal = PLOS Pathogens | volume = 6 | issue = 12 | article-number = e1001222 | date = December 2010 | pmid = 21170303 | pmc = 3000361 | doi = 10.1371/journal.ppat.1001222 | doi-access = free }}</ref> NLRP1B can function as a sensor of bacterial proteases, immune responses are specifically activated by virulence factors.<ref>{{cite journal | vauthors = de Zoete MR, Bouwman LI, Keestra AM, van Putten JP | title = Cleavage and activation of a Toll-like receptor by microbial proteases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 12 | pages = 4968–73 | date = March 2011 | pmid = 21383168 | pmc = 3064367 | doi = 10.1073/pnas.1018135108 | bibcode = 2011PNAS..108.4968D | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sarris PF, Duxbury Z, Huh SU, Ma Y, Segonzac C, Sklenar J, Derbyshire P, Cevik V, Rallapalli G, Saucet SB, Wirthmueller L, Menke FL, Sohn KH, Jones JD | title = A Plant Immune Receptor Detects Pathogen Effectors that Target WRKY Transcription Factors | language = en | journal = Cell | volume = 161 | issue = 5 | pages = 1089–1100 | date = May 2015 | pmid = 26000484 | doi = 10.1016/j.cell.2015.04.024 | doi-access = free }}</ref>

It is not clear what stimuli might activate NLRP1A, the other known functional murine NLRP1 paralog. The study identified a mouse carrying a missense gain-of-function mutation in NLRP1A (Q593P) that active inflammasome responses. The mechanism of wild-type NLRP1A activation is unclear.<ref>{{cite journal | vauthors = Masters SL, Gerlic M, Metcalf D, Preston S, Pellegrini M, O'Donnell JA, McArthur K, Baldwin TM, Chevrier S, Nowell CJ, Cengia LH, Henley KJ, Collinge JE, Kastner DL, Feigenbaum L, Hilton DJ, Alexander WS, Kile BT, Croker BA | title = NLRP1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells | language = en | journal = Immunity | volume = 37 | issue = 6 | pages = 1009–23 | date = December 2012 | pmid = 23219391 | pmc = 4275304 | doi = 10.1016/j.immuni.2012.08.027 }}</ref>

== References == {{reflist}}{{clear}}

== Further reading == {{refbegin|30em}} * {{cite journal | vauthors = Bertin J, DiStefano PS | title = The PYRIN domain: a novel motif found in apoptosis and inflammation proteins | journal = Cell Death and Differentiation | volume = 7 | issue = 12 | pages = 1273–4 | date = December 2000 | pmid = 11270363 | doi = 10.1038/sj.cdd.4400774 | doi-access = free }} * {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–13 | date = April 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }} * {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Research | volume = 7 | issue = 4 | pages = 353–8 | date = April 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }} * {{cite journal | vauthors = Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O | title = Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro | journal = DNA Research | volume = 6 | issue = 1 | pages = 63–70 | date = February 1999 | pmid = 10231032 | doi = 10.1093/dnares/6.1.63 | doi-access = free }} * {{cite journal | vauthors = Hlaing T, Guo RF, Dilley KA, Loussia JM, Morrish TA, Shi MM, Vincenz C, Ward PA | title = Molecular cloning and characterization of DEFCAP-L and -S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins | journal = The Journal of Biological Chemistry | volume = 276 | issue = 12 | pages = 9230–8 | date = March 2001 | pmid = 11076957 | doi = 10.1074/jbc.M009853200 | doi-access = free}} * {{cite journal | vauthors = Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed JC | title = A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis | journal = The Journal of Biological Chemistry | volume = 276 | issue = 12 | pages = 9239–45 | date = March 2001 | pmid = 11113115 | doi = 10.1074/jbc.M006309200 | doi-access = free }} * {{cite journal | vauthors = Martinon F, Hofmann K, Tschopp J | title = The pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation | journal = Current Biology | volume = 11 | issue = 4 | pages = R118-20 | date = February 2001 | pmid = 11250163 | doi = 10.1016/S0960-9822(01)00056-2 | s2cid = 18564343 | doi-access = free | bibcode = 2001CBio...11.R118M }} * {{cite journal | vauthors = Damiano JS, Stehlik C, Pio F, Godzik A, Reed JC | title = CLAN, a novel human CED-4-like gene | journal = Genomics | volume = 75 | issue = 1–3 | pages = 77–83 | date = July 2001 | pmid = 11472070 | doi = 10.1006/geno.2001.6579 }} * {{cite journal | vauthors = Nath SK, Kelly JA, Namjou B, Lam T, Bruner GR, Scofield RH, Aston CE, Harley JB | title = Evidence for a susceptibility gene, SLEV1, on chromosome 17p13 in families with vitiligo-related systemic lupus erythematosus | journal = American Journal of Human Genetics | volume = 69 | issue = 6 | pages = 1401–6 | date = December 2001 | pmid = 11592035 | pmc = 1235552 | doi = 10.1086/324470 }} * {{cite journal | vauthors = Martinon F, Burns K, Tschopp J | title = The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta | journal = Molecular Cell | volume = 10 | issue = 2 | pages = 417–26 | date = August 2002 | pmid = 12191486 | doi = 10.1016/S1097-2765(02)00599-3 | doi-access = free }} * {{cite journal | vauthors = Hiller S, Kohl A, Fiorito F, Herrmann T, Wider G, Tschopp J, Grütter MG, Wüthrich K | title = NMR structure of the apoptosis- and inflammation-related NALP1 pyrin domain | journal = Structure | volume = 11 | issue = 10 | pages = 1199–205 | date = October 2003 | pmid = 14527388 | doi = 10.1016/j.str.2003.08.009 | url = https://edoc.unibas.ch/41059/1/Author_manuscript.pdf }} * {{cite journal | vauthors = Spritz RA, Gowan K, Bennett DC, Fain PR | title = Novel vitiligo susceptibility loci on chromosomes 7 (AIS2) and 8 (AIS3), confirmation of SLEV1 on chromosome 17, and their roles in an autoimmune diathesis | journal = American Journal of Human Genetics | volume = 74 | issue = 1 | pages = 188–91 | date = January 2004 | pmid = 14691733 | pmc = 1181907 | doi = 10.1086/381134 }} * {{cite journal | vauthors = Damiano JS, Oliveira V, Welsh K, Reed JC | title = Heterotypic interactions among NACHT domains: implications for regulation of innate immune responses | journal = The Biochemical Journal | volume = 381 | issue = Pt 1 | pages = 213–9 | date = July 2004 | pmid = 15107016 | pmc = 1133779 | doi = 10.1042/BJ20031506 }} * {{cite journal | vauthors = Liu F, Lo CF, Ning X, Kajkowski EM, Jin M, Chiriac C, Gonzales C, Naureckiene S, Lock YW, Pong K, Zaleska MM, Jacobsen JS, Silverman S, Ozenberger BA | title = Expression of NALP1 in cerebellar granule neurons stimulates apoptosis | journal = Cellular Signalling | volume = 16 | issue = 9 | pages = 1013–21 | date = September 2004 | pmid = 15212762 | doi = 10.1016/j.cellsig.2004.02.006 }} {{refend}}

== External links == * {{PDBe-KB2|Q9C000|NACHT, LRR and PYD domains-containing protein 1}}

{{NOD-like receptors}}

Category:LRR proteins Category:NOD-like receptors