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]

NLRP12
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2L6A, 4XHS
Identifiers
Aliases	NLRP12, CLR19.3, FCAS2, NALP12, PAN6, PYPAF7, RNO, RNO2, NLR family, pyrin domain containing 12, NLR family pyrin domain containing 12
External IDs	OMIM: 609648; MGI: 2676630; HomoloGene: 16972; GeneCards: NLRP12; OMA:NLRP12 - orthologs
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19q13.42 Start 53,793,741 bp[1] End 53,824,394 bp[1]
Gene location (Mouse) Chr. Chromosome 7 (mouse)[2] Band 7|7 A1 Start 3,267,458 bp[2] End 3,298,370 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in blood monocyte granulocyte secondary oocyte buccal mucosa cell trabecular bone bone marrow cell spleen appendix right lung Top expressed in granulocyte liver morula blastocyst epiblast placenta bone marrow yolk sac spleen lung More reference expression data BioGPS n/a
Gene ontology Molecular function nucleotide binding cysteine-type endopeptidase activator activity involved in apoptotic process ATP binding protein binding Cellular component cytoplasm nucleus Biological process dendritic cell migration regulation of cysteine-type endopeptidase activity involved in apoptotic process regulation of I-kappaB kinase/NF-kappaB signaling activation of cysteine-type endopeptidase activity involved in apoptotic process negative regulation of Toll signaling pathway signal transduction negative regulation of NIK/NF-kappaB signaling negative regulation of inflammatory response cellular response to cytokine stimulus negative regulation of I-kappaB kinase/NF-kappaB signaling positive regulation of inflammatory response negative regulation of protein autophosphorylation positive regulation of MHC class I biosynthetic process negative regulation of ERK1 and ERK2 cascade negative regulation of NF-kappaB transcription factor activity negative regulation of signal transduction positive regulation of NIK/NF-kappaB signaling Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 7: 3.27 – 3.3 Mb PubMed search [3] [4]
Wikidata
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NLRP structure

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

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]