Details for: NLRC3

Gene ID: 197358

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: NLRC3

Ensembl ID: ENSG00000167984

Description: NLR family CARD domain containing 3

Cell Significance Landscape

Associated with

  • Cytosolic sensors of pathogen-associated dna
    (R-HSA-1834949)
  • Immune system
    (R-HSA-168256)
  • Innate immune system
    (R-HSA-168249)
  • Irf3-mediated induction of type i ifn
    (R-HSA-3270619)
  • Sting mediated induction of host immune responses
    (R-HSA-1834941)
  • Atp binding
    (GO:0005524)
  • Canonical nf-kappab signal transduction
    (GO:0007249)
  • Centriolar satellite
    (GO:0034451)
  • Cytoplasm
    (GO:0005737)
  • Cytosol
    (GO:0005829)
  • Intracellular membrane-bounded organelle
    (GO:0043231)
  • Intracellular signal transduction
    (GO:0035556)
  • Molecular_function
    (GO:0003674)
  • Negative regulation of canonical nf-kappab signal transduction
    (GO:0043124)
  • Negative regulation of cytokine production involved in inflammatory response
    (GO:1900016)
  • Negative regulation of epithelial cell proliferation
    (GO:0050680)
  • Negative regulation of fibroblast proliferation
    (GO:0048147)
  • Negative regulation of inflammatory response
    (GO:0050728)
  • Negative regulation of innate immune response
    (GO:0045824)
  • Negative regulation of interferon-alpha production
    (GO:0032687)
  • Negative regulation of interferon-beta production
    (GO:0032688)
  • Negative regulation of interleukin-6 production
    (GO:0032715)
  • Negative regulation of nf-kappab transcription factor activity
    (GO:0032088)
  • Negative regulation of nlrp3 inflammasome complex assembly
    (GO:1900226)
  • Negative regulation of non-canonical nf-kappab signal transduction
    (GO:1901223)
  • Negative regulation of phosphatidylinositol 3-kinase/protein kinase b signal transduction
    (GO:0051898)
  • Negative regulation of tumor necrosis factor production
    (GO:0032720)
  • Perinuclear region of cytoplasm
    (GO:0048471)
  • Phosphatidylinositol 3-kinase regulatory subunit binding
    (GO:0036312)
  • Protein binding
    (GO:0005515)
  • T cell activation
    (GO:0042110)

Significant Cells

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

  • CD4-positive, alpha-beta memory T cell CL0000897
    CSI 6.13
    rCSI 4.4%
    PRS 94.31
  • effector CD8-positive, alpha-beta T cell CL0001050
    CSI 4.15
    rCSI 3.16%
    PRS 94.35
  • central memory CD8-positive, alpha-beta T cell CL0000907
    CSI 4.08
    rCSI 2.75%
    PRS 94.5
  • mucosal invariant T cell CL0000940
    CSI 4.07
    rCSI 3.29%
    PRS 91
  • alpha-beta T cell CL0000789
    CSI 3.63
    rCSI 4.25%
    PRS 94.5
  • CD8-positive, CD28-negative, alpha-beta regulatory T cell CL0000920
    CSI 3.59
    rCSI 7.16%
    PRS 93.26
  • double-positive, alpha-beta thymocyte CL0000809
    CSI 3.5
    rCSI 3.57%
    PRS 91.74
  • central memory CD4-positive, alpha-beta T cell CL0000904
    CSI 3.49
    rCSI 2.06%
    PRS 96.04
  • group 3 innate lymphoid cell CL0001071
    CSI 3.47
    rCSI 2.6%
    PRS 88.95
  • mature T cell CL0002419
    CSI 3.42
    rCSI 2.66%
    PRS 94.72
  • plasmablast CL0000980
    CSI 2.47
    rCSI 1.95%
    PRS 87.96
  • ciliated cell CL0000064
    CSI 2.45
    rCSI 3.96%
    PRS 78.8
  • CD8-positive, alpha-beta cytotoxic T cell CL0000794
    CSI 2.35
    rCSI 2.8%
    PRS 95.62
  • effector memory CD8-positive, alpha-beta T cell CL0000913
    CSI 2.29
    rCSI 2.09%
    PRS 93.45
  • activated type II NK T cell CL0000931
    CSI 2.11
    rCSI 2.37%
    PRS 94.11
  • activated CD8-positive, alpha-beta T cell, human CL0001049
    CSI 1.96
    rCSI 3.35%
    PRS 93.71
  • lung resident memory CD8-positive, alpha-beta T cell CL4033039
    CSI 1.37
    rCSI 3.55%
    PRS 95.7
  • effector CD4-positive, alpha-beta T cell CL0001044
    CSI 1.02
    rCSI 2.93%
    PRS 96.56
  • innate lymphoid cell CL0001065
    CSI 0.81
    rCSI 1.67%
    PRS 79.97
  • effector memory CD8-positive, alpha-beta T cell, terminally differentiated CL0001062
    CSI 0.63
    rCSI 3.16%
    PRS 93.63
  • cytotoxic T cell CL0000910
    CSI 0.21
    rCSI 1.23%
    PRS 85.94

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.

Comma-separated if multiple.
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)

Loading network (please wait)...

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 [NLRC3](/details-gene/197358) (NLR Family CARD Domain Containing 3) is a protein-coding gene located on chromosome 16p13.3. As a member of the Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, [NLRC3](/details-gene/197358) functions as a critical intracellular sensor and negative regulator of innate and adaptive immune signaling pathways [Link](https://doi.org/10.1038/nri1086). Its expression is particularly prominent in various subsets of T lymphocytes, including memory and effector T cells, suggesting a key role in modulating T cell function and maintaining immune homeostasis. Mechanistically, [NLRC3](/details-gene/197358) has been shown to attenuate inflammatory responses by inhibiting key signaling pathways, including NF-kappaB and STING-mediated induction of type I interferons. ## Cellular Roles and Expression Landscape The expression profile of [NLRC3](/details-gene/197358) points to a specialized role within the immune system, particularly in the T cell lineage. **Overall**, the gene shows its highest significance in multiple T lymphocyte populations, underscoring its involvement in adaptive immunity. **Key Cellular Contexts:** * **T Lymphocytes:** [NLRC3](/details-gene/197358) is a highly significant marker in [CD4-positive, alpha-beta memory T cell](/details-cell/CL0000897) (CSI: 6.13), [effector CD8-positive, alpha-beta T cell](/details-cell/CL0001050) (CSI: 4.15), [central memory CD8-positive, alpha-beta T cell](/details-cell/CL0000907) (CSI: 4.08), and [mucosal invariant T cell](/details-cell/CL0000940) (CSI: 4.07). Its consistent high significance across memory, effector, and regulatory T cell subsets suggests a fundamental role in controlling T cell activation, differentiation, and function, which is supported by evidence that it negatively regulates T cell function [Link](https://doi.org/10.1074/jbc.m413169200). * **Innate and Other Lymphoid Cells:** Beyond conventional T cells, the gene is also significantly expressed in [group 3 innate lymphoid cell](/details-cell/CL0001071) (CSI: 3.47) and [plasmablast](/details-cell/CL0000980) (CSI: 2.47), indicating a broader role in regulating both innate and adaptive lymphoid cell responses. * **Non-Immune Cells:** The notable significance in [ciliated cell](/details-cell/CL0000064) (CSI: 2.45) is intriguing and may suggest a previously uncharacterized role in mucosal barrier tissues, potentially in modulating local inflammatory responses to environmental stimuli. ## Pathways and Molecular Function [NLRC3](/details-gene/197358) is primarily located in the [cytoplasm](/details-go/GO:0005737) and functions as an inhibitory scaffold protein within key immune signaling cascades. Its molecular activities are consistent with its role as a brake on inflammation. * **Negative Regulation of NF-kappaB Signaling:** A primary function of [NLRC3](/details-gene/197358) is the [negative regulation of canonical nf-kappab signal transduction](/details-go/GO:0043124). It has been shown to attenuate Toll-like receptor (TLR) signaling by interacting with and modifying the signaling adaptor TRAF6, thereby inhibiting downstream NF-kappaB activation [Link](https://doi.org/10.1038/ni.2378). This leads to the suppression of pro-inflammatory cytokines such as IL-6 and TNF-alpha, as indicated by GO terms [negative regulation of interleukin-6 production](/details-go/GO:0032715) and [negative regulation of tumor necrosis factor production](/details-go/GO:0032720). * **Inhibition of STING-Mediated Antiviral Immunity:** [NLRC3](/details-gene/197358) is a key negative regulator of the host response to cytosolic DNA. It directly participates in the [STING mediated induction of host immune responses](/details-pathway/R-HSA-1834941) pathway, where it acts to suppress the production of type I interferons [Link](https://doi.org/10.1016/j.immuni.2014.01.010). This is reflected in its annotation for [negative regulation of interferon-alpha production](/details-go/GO:0032687) and [negative regulation of interferon-beta production](/details-go/GO:0032688). * **Broad Anti-Inflammatory Functions:** The collective evidence from functional annotations and publications supports a broad anti-inflammatory role. [NLRC3](/details-gene/197358) is implicated in the [negative regulation of inflammatory response](/details-go/GO:0050728) and [negative regulation of innate immune response](/details-go/GO:0045824) [Link](https://doi.org/10.1159/000363602), and also appears to restrain cell growth through [negative regulation of epithelial cell proliferation](/details-go/GO:0050680) and the PI3K-AKT signaling pathway. ## Research Directions The function of [NLRC3](/details-gene/197358) as a critical checkpoint in T cell and innate immune signaling opens several avenues for future investigation and therapeutic development. **Testable Hypotheses:** 1. Given its high expression in memory T cell subsets and its known inhibitory function, it is hypothesized that [NLRC3](/details-gene/197358) is essential for maintaining T cell quiescence and preventing memory T cell inflation during chronic antigen exposure. Loss of [NLRC3](/details-gene/197358) in T cells may lead to hyper-activation and premature exhaustion. 2. Based on its role as a STING pathway inhibitor, we hypothesize that downregulation of [NLRC3](/details-gene/197358) in tumor-infiltrating T cells is a mechanism that permits an effective anti-tumor immune response. Conversely, high [NLRC3](/details-gene/197358) expression in these cells could be a marker of T cell dysfunction and a mechanism of immune evasion by tumors. **Proposed Experimental Approach:** To test the second hypothesis, one could employ spatial transcriptomics and single-cell RNA sequencing on human tumor biopsies (e.g., melanoma or lung cancer). This would allow for the precise quantification of [NLRC3](/details-gene/197358) expression within different T cell clusters (e.g., exhausted, effector, memory) and correlation of its expression levels with tumor microenvironment features, patient response to immune checkpoint inhibitors, and signatures of STING pathway activation. Functional validation could be achieved using CRISPR-Cas9 to delete [NLRC3](/details-gene/197358) in T cells used for adoptive cell therapy in mouse tumor models, assessing whether its absence enhances tumor clearance. **Therapeutic Potential:** As a negative regulator of inflammation, [NLRC3](/details-gene/197358) represents a dual-faceted therapeutic target. * **Inhibition:** For oncology, developing small molecule inhibitors or antibody-based therapies to block [NLRC3](/details-gene/197358) function could "release the brakes" on T cell and innate immune responses within the tumor microenvironment. This strategy could synergize with existing immunotherapies, such as checkpoint blockade or STING agonists. * **Activation:** For autoimmune or autoinflammatory diseases characterized by overactive STING or NF-kappaB signaling, developing agonists or gene-based therapies to enhance [NLRC3](/details-gene/197358) expression or activity could be a viable strategy to restore immune homeostasis and suppress pathological inflammation.

Genular Protein ID: 4281694117

Symbol: NLRC3_HUMAN

Name: NLR family CARD domain-containing protein 3

UniProtKB Accession Codes:

Q7RTR2 Q5EY36 Q8NF48 Q8NI01 Q8NI02 Q8TEL3

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEBI 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 6 Ensembl 2 ExpressionAtlas 1 GO 24 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 7 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 4 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 4 RNAct 1 Reactome 1 RefSeq 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TopDownProteomics 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 12766759

Title: NODs: intracellular proteins involved in inflammation and apoptosis.

PubMed ID: 12766759

DOI: 10.1038/nri1086

PubMed ID: 15705585

Title: CATERPILLER 16.2 (CLR16.2), a novel NBD/LRR family member that negatively regulates T cell function.

PubMed ID: 15705585

DOI: 10.1074/jbc.m413169200

PubMed ID: 12693554

Title: Characterization of long cDNA clones from human adult spleen. II. The complete sequences of 81 cDNA clones.

PubMed ID: 12693554

DOI: 10.1093/dnares/10.1.49

PubMed ID: 22863753

Title: The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-kappaB.

PubMed ID: 22863753

DOI: 10.1038/ni.2378

PubMed ID: 24560620

Title: NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING.

PubMed ID: 24560620

DOI: 10.1016/j.immuni.2014.01.010

PubMed ID: 25277106

Title: Overexpressed NLRC3 acts as an anti-inflammatory cytosolic protein.

PubMed ID: 25277106

DOI: 10.1159/000363602

Sequence Information:

  • Length: 1065
  • Mass: 114658
  • Checksum: 9BFFCB21FD134562
  • Sequence:
    • MRKQEVRTGR EAGQGHGTGS PAEQVKALMD LLAGKGSQGS QAPQALDRTP DAPLGPCSND 
SRIQRHRKAL LSKVGGGPEL GGPWHRLASL LLVEGLTDLQ LREHDFTQVE ATRGGGHPAR 
TVALDRLFLP LSRVSVPPRV SITIGVAGMG KTTLVRHFVR LWAHGQVGKD FSLVLPLTFR 
DLNTHEKLCA DRLICSVFPH VGEPSLAVAV PARALLILDG LDECRTPLDF SNTVACTDPK 
KEIPVDHLIT NIIRGNLFPE VSIWITSRPS ASGQIPGGLV DRMTEIRGFN EEEIKVCLEQ 
MFPEDQALLG WMLSQVQADR ALYLMCTVPA FCRLTGMALG HLWRSRTGPQ DAELWPPRTL 
CELYSWYFRM ALSGEGQEKG KASPRIEQVA HGGRKMVGTL GRLAFHGLLK KKYVFYEQDM 
KAFGVDLALL QGAPCSCFLQ REETLASSVA YCFTHLSLQE FVAAAYYYGA SRRAIFDLFT 
ESGVSWPRLG FLTHFRSAAQ RAMQAEDGRL DVFLRFLSGL LSPRVNALLA GSLLAQGEHQ 
AYRTQVAELL QGCLRPDAAV CARAINVLHC LHELQHTELA RSVEEAMESG ALARLTGPAH 
RAALAYLLQV SDACAQEANL SLSLSQGVLQ SLLPQLLYCR KLRLDTNQFQ DPVMELLGSV 
LSGKDCRIQK ISLAENQISN KGAKALARSL LVNRSLTSLD LRGNSIGPQG AKALADALKI 
NRTLTSLSLQ GNTVRDDGAR SMAEALASNR TLSMLHLQKN SIGPMGAQRM ADALKQNRSL 
KELMFSSNSI GDGGAKALAE ALKVNQGLES LDLQSNSISD AGVAALMGAL CTNQTLLSLS 
LRENSISPEG AQAIAHALCA NSTLKNLDLT ANLLHDQGAR AIAVAVRENR TLTSLHLQWN 
FIQAGAAQAL GQALQLNRSL TSLDLQENAI GDDGACAVAR ALKVNTALTA LYLQVASIGA 
SGAQVLGEAL AVNRTLEILD LRGNAIGVAG AKALANALKV NSSLRRLNLQ ENSLGMDGAI 
CIATALSGNH RLQHINLQGN HIGDSGARMI SEAIKTNAPT CTVEM

Genular Protein ID: 3117932842

Symbol: Q8NF06_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q8NF06

Database IDs:

ARBA 1 AlphaFoldDB 1 BioGRID-ORCS 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 GO 3 Gene3D 1 InterPro 5 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PROSITE 2 PeptideAtlas 1 Pfam 3 RefSeq 1 SAM 1

Sequence Information:

  • Length: 660
  • Mass: 72046
  • Checksum: B9B1F8C951D66913
  • Sequence:
    • LSLPSVTYLL LEVIPDSMRK QEVRTGREAG QGHGTGSPAE QVKALMDLLA GKGSQGSHAP 
QALDRTPDAP LGPCSNDSRI QRHRKALLSK VEATRGGGHP ARTVALDRLF LPLSRVSVPP 
RVSITIGVAG MGKTTLVRHF VRLWAHGQVG KDFSLVLPLT FRDLNTHEKL CADRLICSVF 
PHVGEPSLAV AVPARALLIL DGLDECRTPL DFSNTVACTD PKKEIPVDHL ITNIIRGNLF 
PEVSIWITSR PSASGQIPGG LVDRMTEIRG FNEEEIKVCL EQMFPEDQAL LGWMLSQVQA 
DRALYLMCTV PAFCRLTGMA LGHLWRSRTG PQDAELWPPR TLCELYSWYF RMALSGEGQE 
KGKASPRIEQ VAHGGRKMVG TLGRLAFHGL LKKKYVFYEQ DMKAFGVDLA LLQGAPCSCF 
LQREETLASS VAYCFTHLSL QEFVAAAYYY GASRRAIFDL FTESGVSWPR LGFLTHFRSA 
AQRAMQAEDG RLDVFLRFLS GLLSPRVNAL LAGSLLAQGE HQAYRTQVAE LLQGCLRPDA 
AVCARAINVL HCLHELQHTE LARSVEEAME SGALARLTGP AHRAALAYLL QVSDACAQEA 
NLSLSLSQGV LQSLLPQLLY CRKLRWIPGQ GAGAGEGAEE RAEAVPSPPP SFSVSLLGLP