NLRP12

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 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]