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NLRP12

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NLRP12
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNLRP12, CLR19.3, FCAS2, NALP12, PAN6, PYPAF7, RNO, RNO2, NLR family, pyrin domain containing 12, NLR family pyrin domain containing 12
External IDsOMIM: 609648; MGI: 2676630; HomoloGene: 16972; GeneCards: NLRP12; OMA:NLRP12 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

91662

378425

Ensembl

ENSG00000142405

ENSMUSG00000078817

UniProt

P59046

E9Q5R7

RefSeq (mRNA)

NM_001277126
NM_001277129
NM_033297
NM_144687

NM_001033431

RefSeq (protein)

NP_001264055
NP_001264058
NP_653288

NP_001028603

Location (UCSC)Chr 19: 53.79 – 53.82 MbChr 7: 3.27 – 3.3 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain (PYD)-containing protein 12 (NLRP12; also known as NACHT, LRR and PYD domains-containing protein 12 or NALP12) is a protein that in humans is encoded by the NLRP12 gene.[5][6][7]

NLRP structure

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NLRPs, or NALPs, are cytoplasmic innate immune sensors that form a subfamily within the larger CATERPILLER protein family. Most short NLRP proteins, including NLRP12, have an N-terminal pyrin (MEFV; MIM 608107) domain (PYD), followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. The long NALP, NALP1 (MIM 606636), also has a C-terminal extension containing a function to find domain (FIIND) and a caspase recruitment domain (CARD).

Some NLRPs, including NLRP12, are implicated in the activation of proinflammatory caspases (e.g., CASP1; MIM 147678) via their involvement in multiprotein complexes called inflammasomes in context-dependent manners[8] [supplied by OMIM].[7]

NLRP12 function and pathology

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NLRP12 is an innate immune cytosolic sensor and signaling molecule linked to several infections and inflammatory disorders.[9] It can form multimeric protein cell death complexes known as inflammasomes and PANoptosomes in response to specific stimuli.[10][11][12][13] NLRP12 has been reported as both a positive and negative regulator of immune signaling in context-dependent manners.[14][15][16] Infection with certain pathogens, such as Yersinia pestis or Plasmodium chabaudi, activates the NLRP12 inflammasome to release the inflammatory cytokines IL-1β and IL-18, which may help protect against severe infection.[9][11][12][13]

However, NLRP12 acts as a negative regulator of the NF-kB and MAPK signaling pathways following infection with Salmonella enterica serovar Typhimurium, vesicular stomatitis virus, Klebsiella pneumoniae, or Mycobacterium tuberculosis, and in certain malignancies.[9][17] NLRP12 also inhibits signaling in T cells, which is linked to reduced atypical neuroinflammation and atopic dermatitis in mouse models.[18] NLRP12 has also been identified as an innate immune sensor that triggers inflammatory cell death, PANoptosis. PANoptosis is a prominent innate immune, inflammatory, and lytic cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases (RIPKs) through PANoptosomes. PANoptosomes are multi-protein complexes assembled by germline-encoded pattern-recognition receptor(s) (PRRs) (innate immune sensor(s)) in response to pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, cytokines, and homeostatic changes during infections, inflammatory conditions, and cancer.[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]

Through its activation of PANoptosis, NLRP12 has been implicated in pathology when heme is combined with specific components of cellular injury or infection.[12][13] This combination enables NLRP12 to assemble the NLRP12-PANoptosome and trigger cell death via caspase-8 and RIPK3. NLRP12 can also form a PANoptosome complex with other NLRs, including NLRC5  and NLRP3, in response to NAD+ depletion, driving PANoptosis.[19][34] NLRP12 expression is also elevated in patients with hemolytic diseases such as sickle cell disease and malaria, as well as infections such as SARS-CoV-2, influenza, and bacterial pneumonia.[35][36] Deletion of Nlrp12 protects against pathology in animal models of hemolytic disease.[12][13]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000142405 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000078817 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Tschopp J, Martinon F, Burns K (Feb 2003). "NALPs: a novel protein family involved in inflammation". Nat Rev Mol Cell Biol. 4 (2): 95–104. doi:10.1038/nrm1019. PMID 12563287. S2CID 31417018.
  6. ^ Wang L, Manji GA, Grenier JM, Al-Garawi A, Merriam S, Lora JM, Geddes BJ, Briskin M, DiStefano PS, Bertin J (Aug 2002). "PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing". J Biol Chem. 277 (33): 29874–80. doi:10.1074/jbc.M203915200. PMID 12019269.
  7. ^ a b "Entrez Gene: NLRP12 NLR family, pyrin domain containing 12".
  8. ^ Tschopp J, Martinon F, Burns K (2003). "NALPs: a novel protein family involved in inflammation". Nat Rev Mol Cell Biol. 4 (3): 95–104. doi:10.1038/nrm1019. PMID 12563287.
  9. ^ a b c Tuladhar S, Kanneganti T (2020). "NLRP12 in innate immunity and inflammation". Molecular Aspects of Medicine. 76. doi:10.1016/j.mam.2020.100887. PMC 9375713. PMID 32838963.
  10. ^ Vladimer GI, Weng D, Paquette SW, Vanaja SK, Rathinam VA, Aune MH, Conlon JE, Burbage JJ, Proulx MK, Liu Q, Reed G, Mecsas JC, Iwakura Y, Bertin J, Goguen JD, Fitzgerald KA, Lien E (2012). "The NLRP12 Inflammasome Recognizes Yersinia pestis". Immunity. 37 (1): 96–107. doi:10.1016/j.immuni.2012.07.006. PMC 3753114. PMID 22840842.
  11. ^ a b Ataide MA, Andrade WA, Zamboni DS, Wang D, Souza Md, Franklin BS, Elian S, Martins FS, Pereira D, Reed G, Fitzgerald KA, Golenbock DT, Gazzinelli RT (2014-01-16). Sibley LD (ed.). "Malaria-Induced NLRP12/NLRP3-Dependent Caspase-1 Activation Mediates Inflammation and Hypersensitivity to Bacterial Superinfection". PLOS Pathogens. 10 (1): e1003885. doi:10.1371/journal.ppat.1003885. ISSN 1553-7374. PMC 3894209. PMID 24453977.
  12. ^ a b c d Sundaram B, Pandian N, Mall R, Wang Y, Sarkar R, Kim HJ (2023). "NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs". Cell. 186 (13): 2783–2801.e20. doi:10.1016/j.cell.2023.05.005. PMC 10330523. PMID 37267949.
  13. ^ a b c d "St. Jude finds NLRP12 as a new drug target for infection, inflammation and hemolytic diseases". www.stjude.org. Retrieved 2024-02-20.
  14. ^ Pinheiro AS, Eibl C, Ekman-Vural Z, Schwarzenbacher R, Peti W (2011-11-04). "The NLRP12 Pyrin Domain: Structure, Dynamics, and Functional Insights". Journal of Molecular Biology. 413 (4): 790–803. doi:10.1016/j.jmb.2011.09.024. ISSN 0022-2836. PMC 3202057. PMID 21978668.
  15. ^ Tuncer S, Fiorillo MT, Sorrentino R (2014-09-23). "The multifaceted nature of NLRP12". Journal of Leukocyte Biology. 96 (6): 991–1000. doi:10.1189/jlb.3RU0514-265RR. ISSN 0741-5400. PMID 25249449. S2CID 30257891.
  16. ^ Wang L, Manji GA, Grenier JM, Al-Garawi A, Merriam S, Lora JM, Geddes BJ, Briskin M, Distefano PS, Bertin J (2002). "PYPAF7, a Novel PYRIN-containing Apaf1-like Protein That Regulates Activation of NF-κB and Caspase-1-dependent Cytokine Processing". Journal of Biological Chemistry. 277 (33): 29874–29880. doi:10.1074/jbc.M203915200. PMID 12019269.
  17. ^ Allen IC, Wilson JE, Schneider M, Lich JD, Roberts RA, Arthur JC, Woodford RM, Davis BK, Uronis JM, Herfarth HH, Jobin C, Rogers AB, Ting JP (2012). "NLRP12 Suppresses Colon Inflammation and Tumorigenesis through the Negative Regulation of Noncanonical NF-κB Signaling". Immunity. 36 (5): 742–754. doi:10.1016/j.immuni.2012.03.012. PMC 3658309. PMID 22503542.
  18. ^ Lukens JR, Gurung P, Shaw PJ, Barr MJ, Zaki MH, Brown SA, Vogel P, Chi H, Kanneganti TD (2015). "The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells". Immunity. 42 (4): 654–664. doi:10.1016/j.immuni.2015.03.006. PMC 4412374. PMID 25888258.
  19. ^ a b St. Jude Children's Research Hospital (2024-06-14). "St. Jude scientists solve decades long mystery of NLRC5 sensor function in cell death and disease". www.stjude.org. Retrieved 2024-08-13.
  20. ^ "Promising preclinical cancer therapy harnesses a newly discovered cell death pathway". www.stjude.org. 2021-10-19. Retrieved 2024-08-13.
  21. ^ "ZBP1 links interferon treatment and dangerous inflammatory cell death during COVID-19". www.stjude.org. 2022-05-22. Retrieved 2024-08-13.
  22. ^ "The PANoptosome: a new frontier in innate immune responses". www.stjude.org. 2021-09-01.
  23. ^ "In the lab, St. Jude scientists identify possible COVID-19 treatment". www.stjude.org. 2020-11-18. Retrieved 2024-08-13.
  24. ^ "Discovering the secrets of the enigmatic caspase-6". www.stjude.org. 2020-04-15. Retrieved 2024-08-13.
  25. ^ "Breaking the dogma: Key cell death regulator has more than one way to get the job done". 2019-12-23. Retrieved 2024-08-13.
  26. ^ Kuriakose T, Si Ming M, RK Subbarao M, Rajendra K, Kesavardhana S, Place DE, Neale G, Vogel P, Kanneganti TD (2016). "ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways". Science Immunology. 1 (2). doi:10.1126/sciimmunol.aag2045. PMC 5131924. PMID 27917412.
  27. ^ Rajendra K, Sharma BR, Lee E, Banoth B, Malireddi RS, Samir P, Tuladhar S, Mummareddy H, Burton AR, Vogel P, Kanneganti TD (2020). "Interferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer". JCI Insight. 5 (12). doi:10.1172/jci.insight.136720. PMC 7406299. PMID 32554929.
  28. ^ "Diet affects mix of intestinal bacteria and the risk of inflammatory bone disease". www.stjude.org. 2014-10-02. Retrieved 2024-08-13.
  29. ^ Malireddi RK, Rajendra K, Sundaram B, Kancharana B, Lee S, Samir P, Kanneganti TD (2021). "Inflammatory cell death, PANoptosis, mediated by cytokines in diverse cancer lineages inhibits tumor growth". ImmunoHorizons. 5 (7): 568–580. doi:10.4049/immunohorizons.2100059. PMC 8522052. PMID 34290111.
  30. ^ Karki R, Sharma BR, Tuladhar S, Williams EP, Zalduondo L, Samir P, Zheng M, Sundaram B, Banoth B, Malireddi RK, Schreiner P, Naele G, Vogel P, Webby R, Kanneganti TD (2020). "Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes". Cell. 184 (1): 149–168. bioRxiv 10.1101/2020.10.29.361048. doi:10.1016/j.cell.2020.11.025. PMC 7674074. PMID 33278357.
  31. ^ Karki R, Lee S, Raghvendra M, Pandian N, Wang Y, Sharma BR, Malireddi RS, Yang D, Trifkovic S, Steele JA, Connelly JP, Vogel P, Pruitt-Miller SM, Webby R, Kanneganti TD (2022). "ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection". Science Immunology. 7 (74): 74. doi:10.1126/sciimmunol.abo6294. PMC 9161373. PMID 35587515.
  32. ^ Sundaram B, Pandian N, Mall R, Wang Y, Sarkar R, Kim HJ, Malireddi RS, Karki R, Janke LJ, Vogel P, Kanneganti TD (2023). "NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs". Cell. 186 (13): 2783–2801. doi:10.1016/j.cell.2023.05.005. PMC 10330523. PMID 37267949.
  33. ^ Zheng M, Karki R, Vogel P, Kanneganti TD (2020). "Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense". Cell. 181 (3): 674–687. doi:10.1016/j.cell.2020.03.040. PMC 7425208. PMID 32298652.
  34. ^ Sundaram B, Pandian N, Kim HJ, Abdelaal HM, Mall R, Indari O, Sarkar R, Tweedell RE, Alonzo EQ, Klein J, Pruett-Miller SM, Vogel P, Kanneganti TD (2024). "NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation". Cell. 187 (15): 4061–4077. doi:10.1016/j.cell.2024.05.034. PMC 11283362. PMID 38878777.
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  36. ^ Tweedell RE, Kanneganti T (2023). "NLRP12-PANoptosome in haemolytic, infectious and inflammatory diseases". Clinical and Translational Medicine. 13 (9): e1409. doi:10.1002/ctm2.1409. PMC 10497829. PMID 37700491.

Further reading

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