Details for: NLRP12

Gene ID: 91662

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: NLRP12

Ensembl ID: ENSG00000142405

Description: NLR family pyrin domain containing 12

Cell Significance Landscape

Associated with

  • Disease
    (R-HSA-1643685)
  • Infectious disease
    (R-HSA-5663205)
  • Sars-cov-2 activates/modulates innate and adaptive immune responses
    (R-HSA-9705671)
  • Sars-cov-2 infection
    (R-HSA-9694516)
  • Sars-cov-2-host interactions
    (R-HSA-9705683)
  • Sars-cov infections
    (R-HSA-9679506)
  • Viral infection pathways
    (R-HSA-9824446)
  • Activation of cysteine-type endopeptidase activity involved in apoptotic process
    (GO:0006919)
  • Apoptotic process
    (GO:0006915)
  • Atp binding
    (GO:0005524)
  • Cysteine-type endopeptidase activator activity involved in apoptotic process
    (GO:0008656)
  • Cytoplasm
    (GO:0005737)
  • Cytosol
    (GO:0005829)
  • Dendritic cell migration
    (GO:0036336)
  • Erk1 and erk2 cascade
    (GO:0070371)
  • Negative regulation of canonical nf-kappab signal transduction
    (GO:0043124)
  • Negative regulation of cytokine production
    (GO:0001818)
  • Negative regulation of erk1 and erk2 cascade
    (GO:0070373)
  • Negative regulation of inflammatory response
    (GO:0050728)
  • Negative regulation of interleukin-1 production
    (GO:0032692)
  • Negative regulation of interleukin-6 production
    (GO:0032715)
  • Negative regulation of nf-kappab transcription factor activity
    (GO:0032088)
  • Negative regulation of non-canonical nf-kappab signal transduction
    (GO:1901223)
  • Negative regulation of protein autophosphorylation
    (GO:0031953)
  • Negative regulation of signal transduction
    (GO:0009968)
  • Negative regulation of toll signaling pathway
    (GO:0045751)
  • Nucleus
    (GO:0005634)
  • Positive regulation of inflammatory response
    (GO:0050729)
  • Positive regulation of interleukin-1 beta production
    (GO:0032731)
  • Positive regulation of mhc class i biosynthetic process
    (GO:0045345)
  • Positive regulation of non-canonical nf-kappab signal transduction
    (GO:1901224)
  • Protein-macromolecule adaptor activity
    (GO:0030674)
  • Protein binding
    (GO:0005515)
  • Regulation of canonical nf-kappab signal transduction
    (GO:0043122)
  • Regulation of cysteine-type endopeptidase activity involved in apoptotic process
    (GO:0043281)
  • Regulation of inflammatory response
    (GO:0050727)
  • Regulation of interleukin-18 production
    (GO:0032661)
  • Signal transduction
    (GO:0007165)

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • CD14-positive monocyte CL0001054
    CSI 3.05
    rCSI 3.8%
    PRS 99.02
  • promonocyte CL0000559
    CSI 1.5
    rCSI 2.57%
    PRS 97.55
  • CD14-positive, CD16-negative classical monocyte CL0002057
    CSI 0.6
    rCSI 3.64%
    PRS 98.74

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [NLRP12](/details-gene/91662) is a protein-coding gene located on chromosome 19q13.42, which encodes the NLR family pyrin domain containing 12 protein. As a member of the Nod-like receptor (NLR) family of pattern recognition receptors, [NLRP12](/details-gene/91662) plays a crucial role in regulating innate immune responses. Functional annotations strongly suggest its primary role is as a negative regulator of inflammation, particularly through the inhibition of both canonical and non-canonical NF-kappaB signaling pathways. Expression data highlights its significant role within the myeloid lineage, with **Overall** expression being most prominent in [CD14-positive monocyte](/details-cell/CL0001054) and their precursors. This specific expression profile, combined with its inhibitory functions, positions [NLRP12](/details-gene/91662) as a key checkpoint protein for controlling monocyte-driven inflammation. ## Cellular Roles and Expression Landscape The expression profile of [NLRP12](/details-gene/91662) indicates a highly specialized function within the innate immune system, specifically in the monocyte lineage. - **Monocyte Lineage Marker:** **Overall**, the gene shows its highest significance in [CD14-positive monocyte](/details-cell/CL0001054) (CSI: 3.05), followed by their immediate precursors, [promonocyte](/details-cell/CL0000559) (CSI: 1.50), and the major subset of [CD14-positive, CD16-negative classical monocyte](/details-cell/CL0002057) (CSI: 0.60). This concentrated expression pattern suggests that [NLRP12](/details-gene/91662) is a defining component of the molecular machinery in these phagocytic cells, likely involved in maintaining their homeostatic state and modulating their response to inflammatory stimuli. Its role appears to be established early in monocyte development and maintained in mature classical monocytes. - **Immune System Specificity:** The available data points to a specialized role within myeloid cells. While comprehensive data on all cell types is not provided, the strong signal in monocytes suggests that its function is likely distinct from that in lymphoid, epithelial, or stromal cell populations, where its expression is presumably lower. Research has shown that [NLRP12](/details-gene/91662) can promote the degradation of NOD2 in monocytes, thereby facilitating bacterial tolerance [Link](https://doi.org/10.1038/s41467-018-07750-5), further cementing its cell-specific role in microbial sensing and response. ## Pathways and Molecular Function [NLRP12](/details-gene/91662) functions as a multifaceted regulator of key inflammatory and cell death pathways, consistent with its expression in sentinel immune cells. - **Negative Regulation of NF-kappaB Signaling:** The most prominent annotated function of [NLRP12](/details-gene/91662) is the negative regulation of inflammation. It is implicated in the [Negative regulation of canonical nf-kappab signal transduction](/details-go/GO:0043124) and [Negative regulation of non-canonical nf-kappab signal transduction](/details-go/GO:1901223). This inhibitory capacity is critical for preventing excessive inflammation and has been shown to occur through mechanisms such as promoting the degradation of NF-kappaB-inducing kinase (NIK) [Link](https://doi.org/10.4049/jimmunol.179.9.6291). - **Cytokine Production and Inflammatory Response:** Corresponding to its effect on NF-kappaB, [NLRP12](/details-gene/91662) is involved in the [Negative regulation of cytokine production](/details-go/GO:0001818), including interleukin-1 ([GO:0032692](https://www.ebi.ac.uk/QuickGO/term/GO:0032692)) and interleukin-6 ([GO:0032715](https://www.ebi.ac.uk/QuickGO/term/GO:0032715)). This positions it as a brake on the pro-inflammatory cascade initiated by monocytes. However, it also has context-dependent roles in the positive regulation of inflammatory responses ([GO:0050729](https://www.ebi.ac.uk/QuickGO/term/GO:0050729)), suggesting a complex modulatory function rather than simple inhibition. - **Apoptosis and Viral Response:** [NLRP12](/details-gene/91662) is annotated in processes related to apoptosis, such as the [Activation of cysteine-type endopeptidase activity involved in apoptotic process](/details-go/GO:0006919), which may be linked to its ability to regulate caspase-1 [Link](https://doi.org/10.1074/jbc.m203915200). Furthermore, Reactome pathway analysis highlights its involvement in the host response to viral infections, including [Sars-cov-2 infection](/details-pathway/R-HSA-9694516), suggesting a role in modulating immune reactions to viral pathogens [Link](https://doi.org/10.1016/j.chom.2019.02.013). ## Research Directions The specific expression of [NLRP12](/details-gene/91662) in monocytes and its role as an inflammatory regulator offer several avenues for future investigation. 1. **Hypothesis 1:** Given its role as a negative regulator of NF-kappaB and its high expression in monocytes, we hypothesize that loss-of-function mutations in [NLRP12](/details-gene/91662) lead to a hyper-inflammatory phenotype in monocytes, characterized by exaggerated cytokine production in response to TLR ligands. This would provide a cellular mechanism for the hereditary periodic fever syndromes associated with [NLRP12](/details-gene/91662) mutations [Link](https://doi.org/10.1073/pnas.0708616105). 2. **Hypothesis 2:** Based on its connection to viral infection pathways ([R-HSA-9824446](https://reactome.org/content/detail/R-HSA-9824446)) and its regulation of RIG-I signaling [Link](https://doi.org/10.1016/j.chom.2019.02.013), we hypothesize that [NLRP12](/details-gene/91662) functions as a crucial checkpoint in monocytes to temper the antiviral interferon response, thereby preventing immunopathology and cytokine storm during acute viral infections like SARS-CoV-2. **Proposed Experiment:** To test Hypothesis 1, one could utilize CRISPR-Cas9 to generate an [NLRP12](/details-gene/91662) knockout (KO) in a human monocytic cell line (e.g., THP-1) and in primary human monocytes derived from healthy donors. Wild-type (WT) and KO cells would be stimulated with a panel of Toll-like receptor (TLR) agonists, such as LPS (TLR4) or R848 (TLR7/8). The inflammatory response could be quantified by measuring the secretion of key cytokines (e.g., IL-1β, IL-6, TNF-α) using ELISA or a multiplex bead array. Additionally, NF-kappaB pathway activation could be assessed by measuring the phosphorylation of p65 and IκBα via western blotting. A significantly higher cytokine output and more robust NF-kappaB activation in KO cells compared to WT controls would support the hypothesis that [NLRP12](/details-gene/91662) is a critical brake on monocyte-mediated inflammation. **Therapeutic Potential:** As an intracellular protein, [NLRP12](/details-gene/91662) is not a direct target for antibody-based therapies. However, its function as an inhibitor of pro-inflammatory pathways makes it a compelling target for small-molecule drugs. In autoinflammatory diseases or conditions of excessive inflammation driven by monocytes, developing a small-molecule agonist that enhances or stabilizes the inhibitory function of [NLRP12](/details-gene/91662) could be a viable therapeutic strategy. Such a compound would aim to **activate** this natural brake on the immune system, potentially offering a targeted approach to treating conditions like familial cold autoinflammatory syndrome or sepsis-associated cytokine storms.

Genular Protein ID: 1009685049

Symbol: NAL12_HUMAN

Name: NACHT, LRR and PYD domains-containing protein 12

UniProtKB Accession Codes:

P59046 A8MTQ2 B3KTE7 Q8NEU4 Q9BY26

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CDD 2 CTD 1 ChEBI 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 11 Ensembl 3 EvolutionaryTrace 1 ExpressionAtlas 1 GO 28 Gene3D 3 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 10 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 6 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 6 RNAct 1 Reactome 1 RefSeq 3 SMART 3 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 TreeFam 1 UCSC 1 UniProtKB 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 12019269

Title: PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing.

PubMed ID: 12019269

DOI: 10.1074/jbc.m203915200

PubMed ID: 12563287

Title: NALPs: a novel protein family involved in inflammation.

PubMed ID: 12563287

DOI: 10.1038/nrm1019

PubMed ID: 11167794

Title: Identification and characterization of a novel gene that is upregulated in leukaemia cells by nitric oxide.

PubMed ID: 11167794

DOI: 10.1046/j.1365-2141.2001.02491.x

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 17237370

Title: Monarch-1 suppresses non-canonical NF-kappaB activation and p52-dependent chemokine expression in monocytes.

PubMed ID: 17237370

DOI: 10.4049/jimmunol.178.3.1256

PubMed ID: 17947705

Title: Heat shock protein 90 associates with monarch-1 and regulates its ability to promote degradation of NF-kappaB-inducing kinase.

PubMed ID: 17947705

DOI: 10.4049/jimmunol.179.9.6291

PubMed ID: 18160710

Title: ATP binding by monarch-1/NLRP12 is critical for its inhibitory function.

PubMed ID: 18160710

DOI: 10.1128/mcb.01468-07

PubMed ID: 18230725

Title: Mutations in NALP12 cause hereditary periodic fever syndromes.

PubMed ID: 18230725

DOI: 10.1073/pnas.0708616105

PubMed ID: 30559449

Title: Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial tolerance and colonization by enteropathogens.

PubMed ID: 30559449

DOI: 10.1038/s41467-018-07750-5

PubMed ID: 30902577

Title: NLRP12 Regulates Anti-viral RIG-I Activation via Interaction with TRIM25.

PubMed ID: 30902577

DOI: 10.1016/j.chom.2019.02.013

PubMed ID: 21978668

Title: The NLRP12 pyrin domain: structure, dynamics, and functional insights.

PubMed ID: 21978668

DOI: 10.1016/j.jmb.2011.09.024

PubMed ID: 28112203

Title: Design of an expression system to enhance MBP-mediated crystallization.

PubMed ID: 28112203

DOI: 10.1038/srep40991

Sequence Information:

  • Length: 1061
  • Mass: 120173
  • Checksum: 8C10AFE4907C131B
  • Sequence:
    • MLRTAGRDGL CRLSTYLEEL EAVELKKFKL YLGTATELGE GKIPWGSMEK AGPLEMAQLL 
ITHFGPEEAW RLALSTFERI NRKDLWERGQ REDLVRDTPP GGPSSLGNQS TCLLEVSLVT 
PRKDPQETYR DYVRRKFRLM EDRNARLGEC VNLSHRYTRL LLVKEHSNPM QVQQQLLDTG 
RGHARTVGHQ ASPIKIETLF EPDEERPEPP RTVVMQGAAG IGKSMLAHKV MLDWADGKLF 
QGRFDYLFYI NCREMNQSAT ECSMQDLIFS CWPEPSAPLQ ELIRVPERLL FIIDGFDELK 
PSFHDPQGPW CLCWEEKRPT ELLLNSLIRK KLLPELSLLI TTRPTALEKL HRLLEHPRHV 
EILGFSEAER KEYFYKYFHN AEQAGQVFNY VRDNEPLFTM CFVPLVCWVV CTCLQQQLEG 
GGLLRQTSRT TTAVYMLYLL SLMQPKPGAP RLQPPPNQRG LCSLAADGLW NQKILFEEQD 
LRKHGLDGED VSAFLNMNIF QKDINCERYY SFIHLSFQEF FAAMYYILDE GEGGAGPDQD 
VTRLLTEYAF SERSFLALTS RFLFGLLNEE TRSHLEKSLC WKVSPHIKMD LLQWIQSKAQ 
SDGSTLQQGS LEFFSCLYEI QEEEFIQQAL SHFQVIVVSN IASKMEHMVS SFCLKRCRSA 
QVLHLYGATY SADGEDRARC SAGAHTLLVQ LPERTVLLDA YSEHLAAALC TNPNLIELSL 
YRNALGSRGV KLLCQGLRHP NCKLQNLRLK RCRISSSACE DLSAALIANK NLTRMDLSGN 
GVGFPGMMLL CEGLRHPQCR LQMIQLRKCQ LESGACQEMA SVLGTNPHLV ELDLTGNALE 
DLGLRLLCQG LRHPVCRLRT LWLKICRLTA AACDELASTL SVNQSLRELD LSLNELGDLG 
VLLLCEGLRH PTCKLQTLRL GICRLGSAAC EGLSVVLQAN HNLRELDLSF NDLGDWGLWL 
LAEGLQHPAC RLQKLWLDSC GLTAKACENL YFTLGINQTL TDLYLTNNAL GDTGVRLLCK 
RLSHPGCKLR VLWLFGMDLN KMTHSRLAAL RVTKPYLDIG C