NLRP12
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
[edit]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
[edit]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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Further reading
[edit]- Shami PJ, Kanai N, Wang LY, et al. (2001). "Identification and characterization of a novel gene that is upregulated in leukaemia cells by nitric oxide". Br. J. Haematol. 112 (1): 138–47. doi:10.1046/j.1365-2141.2001.02491.x. PMID 11167794. S2CID 44981142.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Williams KL, Taxman DJ, Linhoff MW, et al. (2003). "Cutting edge: Monarch-1: a pyrin/nucleotide-binding domain/leucine-rich repeat protein that controls classical and nonclassical MHC class I genes". J. Immunol. 170 (11): 5354–8. doi:10.4049/jimmunol.170.11.5354. PMID 12759408.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Williams KL, Lich JD, Duncan JA, et al. (2006). "The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals". J. Biol. Chem. 280 (48): 39914–24. doi:10.1074/jbc.M502820200. PMC 4422647. PMID 16203735.
- Lich JD, Williams KL, Moore CB, et al. (2007). "Monarch-1 suppresses non-canonical NF-kappaB activation and p52-dependent chemokine expression in monocytes". J. Immunol. 178 (3): 1256–60. doi:10.4049/jimmunol.178.3.1256. PMID 17237370.
- Arthur JC, Lich JD, Aziz RK, et al. (2007). "Heat shock protein 90 associates with monarch-1 and regulates its ability to promote degradation of NF-kappaB-inducing kinase". J. Immunol. 179 (9): 6291–6. doi:10.4049/jimmunol.179.9.6291. PMID 17947705.
- Chen L, Wilson JE, Koenigsknecht MJ, et al. (2017). "NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth". Nature Immunology. 18 (5): 541–551. doi:10.1038/ni.3690. PMC 5395345. PMID 28288099.