1. Function

2. Mechanism of activation

3. Interactions

4. Variants of NLRP1 in mice

5. References

6. Further reading

NLRP1 encodes NACHT, LRR, FIIND, CARD domain and PYD domains-containing protein 1 in humans ^[1][2][3]. NLRP1 was the first protein shown to form an inflammasome ^[4]. NLRP1 is expressed by a variety of cell types, which are predominantly hematopoietic. The expression is also seen within glandular epithelial structures including the lining of the small intestine, stomach ^[5]. NLRP1 polymorphisms are associated with skin extra-intestinal manifestations in CD ^[5]. 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^[6]. Variants of mouse NLRP1 were found to be activated upon N-terminal cleavage by the protease in anthrax lethal factor ^[4].

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 apoptosis 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 ^[3].

Mechanism of activation

NLRP1 activates a antibacterial immune response. Antibacterial immune response compensates for the loss of the MAP kinase response. Humans produce NLRP1, but human NLRP1 is activated by lethal factor ^[4]. NLRP1 could be activated by proteolytic cleavage resulting in the removal of an auto-inhibitory PYD ^[4]. But the mechanism of human NLRP1 activation and the function in immunity is not unclear ^[4].

Interactions

NLRP1 has been shown to interact with caspase 9^[7][8] and APAF1 ^[7].

Variants of NLRP1 in mice

Mice have three paralogs of the Nlrp1 gene (Nlrp1a, b, c). Nlrp1c is a pseudogene ^[9]. 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 ^[10]. 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^[11][12]. LF also directly cleaves NLRP1B proximal to its N-terminus, it is necessary and sufficient for NLRP1B inflammasome formation and CASP1 activation ^[13]. Activation of NLRP1B-dependent inflammasome responses appears in host defense with mechanism like IL-1β and neutrophils ^[14][15]. NLRP1B can function as a sensor of bacterial proteases, immune responses are specifically activated by virulence factors ^[16][17].

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 ^[18].

References

Further reading

• {{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 }}
• {{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 }}
• {{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 }}
• {{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 }}
• {{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 }}
• {{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 }}
• {{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 }}
• {{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 }}

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