Affinage

NCR1

Natural cytotoxicity triggering receptor 1 · UniProt O76036

Length
304 aa
Mass
34.5 kDa
Annotated
2026-04-29
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NCR1 (NKp46) is a principal activating receptor on natural killer cells that integrates innate immune surveillance of infected, stressed, and transformed cells through recognition of a broad ligand repertoire. The receptor contains two extracellular C2-type Ig-like domains and signals through ITAM-containing adaptors CD3ζ and FcεRIγ, recruited via a charged transmembrane arginine residue; engagement triggers calcium mobilization, F-actin reorganization, lytic granule polarization at the immune synapse, and IFN-γ secretion (PMID:9730896, PMID:15356098, PMID:26441997, PMID:18713971). NKp46 recognizes viral hemagglutinins via α2,6-linked sialic acid on its membrane-proximal domain, heparan sulfate proteoglycans through a basic-residue cluster (K133–K146) in the D2 domain, surface vimentin on Mycobacterium tuberculosis–infected monocytes, fungal Epa adhesins, complement factor properdin, and — as the key endogenous danger ligand — ecto-calreticulin (P domain) exposed on ER-stressed, senescent, and transformed cells (PMID:11234016, PMID:16262248, PMID:17056548, PMID:27736647, PMID:28480349, PMID:37020026). NKp46-driven IFN-γ remodels tumor architecture by upregulating fibronectin 1 to suppress metastasis; its signaling threshold is calibrated by NKG2D-dependent CD3ζ levels, while its activity is negatively regulated by neuraminidase-mediated desialylation, cathepsin G proteolysis, adenosine/PKA-I signaling, and transcriptional control by RUNX3 and STAT3 (PMID:29329948, PMID:30224819, PMID:23602571, PMID:27587403, PMID:22253448).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Identification of NKp46 as a novel Ig-superfamily activating receptor on NK cells resolved the molecular basis of natural cytotoxicity receptor-mediated tumor lysis.

    Evidence cDNA cloning, domain analysis, and blocking-antibody cytotoxicity assays in human NK cells

    PMID:9730896

    Open questions at the time
    • Endogenous tumor-cell ligand unknown
    • Signaling adaptor association inferred from charged TM Arg but not biochemically demonstrated for human NKp46
  2. 1999 High

    Demonstration that NKp46 surface density quantitatively determines natural cytotoxicity established it as the dominant triggering receptor on NK cells, while cloning of the murine ortholog enabled genetic studies.

    Evidence Correlation of NKp46 density with lysis across multiple NK clones; cDNA cloning and chromosomal mapping of mouse Ncr1

    PMID:10092106 PMID:10359120

    Open questions at the time
    • No ligand identified on target cells
    • Downstream signaling cascade not mapped
  3. 2001 High

    Discovery that NKp46 binds influenza hemagglutinin via sialylated oligosaccharides revealed the first defined NKp46 ligand and a glycan-dependent recognition mechanism for viral pathogen detection.

    Evidence NKp46-Ig fusion protein binding assays with sialic acid dependency experiments

    PMID:11234016

    Open questions at the time
    • Structural basis of HA–NKp46 interaction unresolved
    • Tumor ligand still unidentified
  4. 2003 High

    Mutagenesis pinpointed the membrane-proximal D2 domain and Thr225 as critical for ligand engagement, showing that viral HA and tumor ligands are recognized through overlapping but mechanistically distinct surfaces on NKp46.

    Evidence Site-directed mutagenesis and domain-swap experiments with binding assays

    PMID:14504081

    Open questions at the time
    • Tumor ligand identity still unknown
    • No crystal structure of ligand-bound NKp46
  5. 2004 High

    Identification of heparan sulfate proteoglycans as tumor-cell ligands and biochemical confirmation of CD3ζ/FcεRIγ adaptor association established the dual recognition and signaling framework for NKp46.

    Evidence HSPG-deficient cells and siRNA knockdown with NK cytotoxicity assays; co-immunoprecipitation of rat NKp46 with CD3ζ and FcεRIγ

    PMID:15294952 PMID:15356098

    Open questions at the time
    • Specific HSPG ligand on tumor cells not identified
    • ITAM phosphorylation cascade downstream of NKp46 not mapped
  6. 2005 High

    Mapping the heparin-binding site to a defined basic-residue cluster (K133–K146) in D2 with an octasaccharide minimum epitope provided the first molecular-resolution picture of NKp46–glycan recognition.

    Evidence Site-directed mutagenesis with quantitative KD measurements and monodesulfated heparin oligomers

    PMID:16262248

    Open questions at the time
    • No co-crystal structure to validate the binding mode
    • In vivo relevance of HSPG recognition not tested
  7. 2006 High

    Three advances converged: vimentin was identified as an NKp46 ligand on Mtb-infected monocytes, Ncr1-knockout mice proved NKp46 essential for influenza clearance in vivo, and adenosine/PKA-I signaling was shown to suppress NKp46-mediated cytotoxicity.

    Evidence MS-based ligand identification with reconstitution in CHO cells; Ncr1-GFP knock-in mice with lethal influenza phenotype; PKA subunit dissection with NKp46-crosslinking assays

    PMID:16565719 PMID:17056548 PMID:17337770

    Open questions at the time
    • Whether vimentin recognition extends beyond Mtb-infected cells unclear
    • Mechanism by which PKA-I inhibits NKp46 signaling not defined at the molecular level
  8. 2008 High

    Functional segregation of NKp46 (cytotoxicity, granule polarization) versus NKp30 (cytokine production) in decidual NK cells revealed receptor-specific signaling programs downstream of distinct NCRs.

    Evidence Receptor-specific mAb engagement with calcium flux, degranulation, and cytokine readouts in human decidual NK cells

    PMID:18713971

    Open questions at the time
    • Molecular basis for signaling divergence between NKp46 and NKp30 despite shared CD3ζ adaptor not explained
  9. 2009 High

    NKp46 was shown to recognize ligands on pancreatic beta cells driving type 1 diabetes and on lymphoma cells controlling tumor rejection, broadening its role beyond infection to autoimmunity and cancer immunosurveillance.

    Evidence Ncr1-knockout mice in streptozotocin and NOD diabetes models with soluble NKp46 intervention; Ncr1-knockout mice failing to reject PD1.6 lymphoma in vivo

    PMID:19201876 PMID:20023661

    Open questions at the time
    • Beta-cell NKp46 ligand identity unknown
    • Lymphoma NKp46 ligand identity unknown
  10. 2011 High

    Multiple studies refined NKp46 biology: the D2 domain/stalk glycosylation sites (Thr125, Asn216) were critical for beta-cell recognition, poxviral HA was identified as a ligand exploited for immune evasion, and NKp46 was shown to mediate NK killing of hepatic stellate cells limiting liver fibrosis.

    Evidence Mutagenesis of NKp46 glycosylation sites; NCR-silenced NK cells and reporter assays for poxviral HA; Ncr1-KO mice in CCl4 fibrosis model

    PMID:21849674 PMID:21901096 PMID:22198715

    Open questions at the time
    • Hepatic stellate cell NKp46 ligand unidentified
    • Whether beta-cell and tumor ligands are the same entity unresolved
  11. 2012 High

    NKp46 was found to form microclusters at the immune synapse driving F-actin and lytic granule polarization, to control metastasis in melanoma and lung carcinoma, to be transcriptionally regulated by RUNX3, and — paradoxically — to set a tonic inhibitory threshold via Helios silencing.

    Evidence Super-resolution imaging with NKp46 gain/loss-of-function; Ncr1-KO mice in spontaneous metastasis models; EMSA and reporter assays for RUNX3; ENU mutagenesis screen identifying Ncr1 loss-of-function hyperresponsiveness

    PMID:22253448 PMID:22267813 PMID:22308311 PMID:26441997

    Open questions at the time
    • Mechanism of Helios-mediated tonic inhibition downstream of NKp46 not fully dissected
    • Metastasis-controlling NKp46 ligands on B16 and D122 cells unknown
  12. 2013 High

    Viral neuraminidase was shown to desialylate NKp46 as an immune evasion strategy, and NA inhibitors were found to boost NKp46-mediated recognition of infected cells, linking antiviral pharmacology to NKp46 function.

    Evidence NA inhibitor treatment preserving NKp46 sialylation in vivo and in vitro influenza models

    PMID:23602571

    Open questions at the time
    • Whether NA inhibitor-mediated NKp46 preservation contributes to clinical efficacy in humans not tested
  13. 2016 High

    NKp46 was identified as a pattern recognition receptor for fungal adhesins (Epa1/6/7 of Candida glabrata), and cathepsin G was found to proteolytically cleave NKp46 impairing its function, revealing both a new pathogen-sensing role and an endogenous regulatory mechanism.

    Evidence Ncr1-KO mice in systemic C. glabrata infection; mass spectrometry identification of cathepsin G cleavage with protease inhibitor validation

    PMID:27587403 PMID:27736647

    Open questions at the time
    • Cathepsin G cleavage site on NKp46 not mapped at the amino acid level
    • Whether fungal adhesin recognition depends on glycosylation of NKp46 not tested
  14. 2018 High

    NKp46-driven IFN-γ was shown to remodel tumor architecture by upregulating fibronectin 1 to suppress metastasis, and NKG2D was found to calibrate NKp46 signaling thresholds via DAP12-dependent regulation of CD3ζ levels, establishing a cross-receptor tuning mechanism.

    Evidence Ncr1-KO and Ncr1-overexpression transgenic mice with in vivo tumor imaging; Klrk1-KO and DAP12-KO mice with CD3ζ quantification and NCR1-specific functional assays

    PMID:29329948 PMID:30224819

    Open questions at the time
    • Molecular mechanism by which IFN-γ induces FN1 in tumor stroma not defined
    • How DAP12 sets CD3ζ levels molecularly not elucidated
  15. 2023 High

    Identification of ecto-calreticulin as the long-sought endogenous NKp46 ligand unified decades of observations by explaining how NKp46 detects ER-stressed, infected, senescent, and transformed cells through a single danger-signal mechanism.

    Evidence Co-IP and domain mapping (P domain of CRT), CRISPR knockouts of CALR and NCR1, immune synapse imaging, and in vivo melanoma and RAS-driven lung cancer models

    PMID:37020026

    Open questions at the time
    • Whether ecto-CRT accounts for all previously described NKp46 tumor-ligand interactions (e.g. beta cells, HSC) remains untested
    • Structural basis of NKp46–CRT P-domain interaction not resolved at atomic level
    • Relative contribution of ecto-CRT versus HSPG or vimentin ligands in different disease contexts not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic-resolution structure of NKp46 bound to ecto-calreticulin, the identity of NKp46 ligands on pancreatic beta cells and hepatic stellate cells, and the precise mechanism by which NKp46 tonic signaling via Helios restrains NK cell activation.
  • No co-crystal structure of NKp46 with any ligand
  • Beta-cell and HSC ligands remain undefined
  • Helios-dependent tonic inhibition pathway not molecularly dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 6 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 10 R-HSA-162582 Signal Transduction 4
Partners
CALRCD247CFPFCER1GRUNX3VIM

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 NKp46 (NCR1) was molecularly cloned and identified as a novel immunoglobulin superfamily member with two C2-type Ig-like extracellular domains, a transmembrane region containing a positively charged Arg residue (likely mediating association with CD3ζ), and a 30-amino acid cytoplasmic tail lacking ITAM motifs. It functions as a major activating receptor mediating NK cell lysis of tumor cells. cDNA cloning, domain analysis, functional NK cytotoxicity assays with blocking antibodies The Journal of experimental medicine High 9730896
1999 NKp46 surface density directly correlates with NK cell natural cytotoxicity against HLA class I-unprotected allogeneic, autologous, and xenogeneic target cells; antibody-mediated masking of NKp46 inhibits cytolysis, establishing NKp46 as the primary triggering receptor for natural cytotoxicity. NK clone phenotyping, antibody-blocking cytotoxicity assays, correlation analysis European journal of immunology High 10359120
1999 The murine NKp46 homologue (MAR-1/NCR1) was identified on chromosome 7, encodes a type I transmembrane glycoprotein with two C2-type Ig-like domains and a charged Arg in the transmembrane region, suggesting association with ITAM-containing adaptor proteins in a multimeric complex. cDNA cloning, chromosomal mapping, RT-PCR, cell surface expression analysis European journal of immunology High 10092106
2001 NKp46 directly binds to influenza virus hemagglutinin (HA) and parainfluenza virus hemagglutinin-neuraminidase via sialylated oligosaccharides on NKp46, enabling NK cell recognition and lysis of virus-infected cells. Soluble NKp46-Ig fusion protein binding assays, antibody blocking of NK lysis, sialic acid dependency experiments Nature High 11234016
2002 NKp46 mediates NK cell lysis of Mycobacterium tuberculosis-infected monocytes; NKp46 mRNA is upregulated in NK cells upon infection, and anti-NKp46 antisera markedly inhibit lysis of infected monocytes. NK cytotoxicity assay with antibody blocking, RT-PCR for NKp46 mRNA Journal of immunology Medium 11907104
2003 NKp46 recognition of viral hemagglutinins is direct and mainly mediated via α2,6-linked sialic acid on NKp46; the membrane-proximal domain of NKp46 is critical for ligand recognition; Thr225 plays a dual role in interactions with both viral hemagglutinins and unknown tumor ligands through different mechanisms. Site-directed mutagenesis, sialic acid linkage analysis, domain-swap experiments, binding assays Blood High 14504081
2004 NKp46 recognizes cell surface heparan sulfate proteoglycans (HSPGs) as ligands on tumor cells; 6-O-sulfation and N-acetylation of the heparan sulfate glucosamine unit affect recognition; cells lacking surface heparan sulfate or with suppressed glypican-1 show reduced NKp46 recognition and NK-mediated lysis. HSPG-deficient cells, enzymatic removal of HS, glypican-1 siRNA suppression, NK cytotoxicity assays Journal of immunology High 15294952
2004 Rat NKp46 is an activating receptor that co-immunoprecipitates with the ITAM-containing adaptor proteins CD3ζ and FcεRIγ, indicating it activates NK cell cytotoxicity through association with these signaling adaptors. Immunoprecipitation, Western blot, redirected lysis assay Journal of leukocyte biology High 15356098
2005 The heparin/heparan sulfate binding site of NKp46 is a continuous region containing basic amino acids K133, R136, H139, R142, and K146 in the D2 domain; the minimal heparin epitope recognized is eight saccharides; specific O-sulfation, N-sulfation, and N-acetylation states are required for binding. Site-directed mutagenesis, heparin binding assays with KD determination, testing of selective monodesulfated heparin oligomers Biochemistry High 16262248
2006 Vimentin expressed on the surface of M. tuberculosis-infected monocytes serves as a ligand for NKp46; anti-vimentin antiserum inhibits NK lysis of infected monocytes; recombinant vimentin directly binds NKp46 fusion protein; CHO cells transfected with vimentin are lysed in an NKp46-dependent manner. Immunoprecipitation/mass spectrometry ligand identification, ELISA and Far Western binding assays, antibody blocking, vimentin transfection into CHO cells Journal of immunology High 17056548
2006 NCR1 (mouse NKp46) is critical for in vivo eradication of influenza virus; Ncr1-knockout mice suffer lethal influenza infection; NK cells accumulate at the site of influenza infection as tracked by GFP reporter. Ncr1 gene replacement with GFP reporter (knockout mouse), influenza infection survival experiments, in vivo NK cell tracking Nature immunology High 16565719
2006 Adenosine suppresses NKp46-mediated NK cell cytotoxicity and cytokine production through A2A adenosine receptor signaling, cAMP elevation, and PKA type I activation; this mechanism may protect tumors from NK cell-mediated destruction. NK cytotoxicity assay with NKp46 receptor crosslinking, PKA subunit blocking, cAMP measurement Immunologic research Medium 17337770
2008 In human decidual NK cells, NKp46 engagement (but not NKp30) specifically triggers calcium mobilization, perforin polarization, granule exocytosis, and target cell lysis; NKp30 engagement triggers cytokine production (IFN-γ, TNF-α, MIP-1α, MIP-1β, GM-CSF) but not cytotoxicity; NKp46-mediated cytotoxicity is co-activated by CD2 and blocked by NKG2A co-engagement. mAb-specific receptor engagement, calcium flux measurement, granule exocytosis assay, target cell lysis assay, cytokine measurement Journal of immunology High 18713971
2009 NKp46 recognizes an unknown ligand on pancreatic beta cells; NKp46-deficient mice develop less type 1 diabetes after low-dose streptozotocin; soluble NKp46 injection into NOD mice during early insulitis prevents diabetes development; NK cells appear in the pancreas when insulitis progresses to diabetes. Ncr1 knockout mice, streptozotocin diabetes model, NOD mouse insulitis, in vivo soluble NKp46 protein injection Nature immunology High 20023661
2009 NKp30 and NKp46 bind to heparan sulfate/heparin structures with preference for highly charged sequences; NKp46 has approximately 10-fold lower affinity for synthetic HS/heparin than NKp30 or NKp44; binding of NCRs to HS correlates with NK cell activation. Microarray and surface plasmon resonance with a library of HS/heparin oligosaccharides, NK cell activation assays Journal of proteome research High 19196184
2009 In vitro, NKp46-mediated NK killing of NKp46-ligand-expressing lymphoma cells (PD1.6 line) is NKp46-dependent; in vivo, Ncr1-knockout mice fail to reject PD1.6 lymphoma tumors that wild-type mice clear, revealing a crucial role for NKp46/NCR1 in eradication of certain lymphoma cells. Cell reporter assay for NCR1 ligand identification, in vitro NK cytotoxicity assay, in vivo tumor growth in Ncr1gfp/gfp knockout mice Journal of immunology High 19201876
2011 NKp46 recognizes an unknown ligand on both human and murine hepatic stellate cells (HSC); NCR1-deficient mice display enhanced liver fibrosis in the CCl4 model; murine and human HSC are killed in an NKp46/NCR1-dependent manner in vitro; NKp46-Fc fusion proteins detect HSC ligand expression. Ncr1 knockout mice with CCl4 fibrosis model, in vitro NK killing assays with blocking, NKp46-Fc fusion protein staining Gut High 22198715
2011 NKp46 directly mediates NK-induced neutrophil apoptosis in a cell-contact-dependent and caspase-dependent manner via the Fas pathway; blocking NKp46 with antibodies inhibits this NK-neutrophil interaction. Co-culture experiments, caspase activation assays, blocking antibody experiments, CD56 depletion controls Journal of immunology Medium 22231698
2011 Recognition and killing of human and murine pancreatic beta cells by NKp46 is confined to the membrane-proximal domain and stalk region of NKp46; glycosylated residues Thr125 and Asn216 of NKp46 are critical for beta cell ligand recognition. Domain-swap constructs, site-directed mutagenesis of glycosylation sites, NK cytotoxicity assays Journal of immunology High 21849674
2011 Poxviral hemagglutinin (HA from vaccinia and ectromelia viruses) is a ligand for both NKp30 and NKp46; poxviral HA on infected cells or as soluble protein blocks NKp30-triggered activation but stimulates NKp46 activation; this differential effect represents a viral immune evasion strategy. NCR-silenced NK cells, NCR-CD3ζ reporter cells, recombinant soluble HA binding and functional assays PLoS pathogens High 21901096
2012 A loss-of-function mutation in Ncr1 encoding NKp46 results in hyperresponsive NK cells with increased viral resistance; NKp46 normally down-regulates NK cell activity through silencing of the Helios transcription factor; NKp46 signaling is critical for subsequent optimal adaptive T cell responses to viral and bacterial infections. ENU mutagenesis screen, whole-genome sequencing, Helios transcription factor analysis, in vivo infection models Science High 22267813
2012 NKp46 forms microclusters at the NK immune synapse; overexpression of NKp46 increases F-actin mesh accumulation at the synapse; knockdown of NKp46 in primary NK cells decreases F-actin recruitment; NKp46 expression linearly correlates with lytic granule polarization to the immune synapse. Live cell imaging, super-resolution microscopy, NKp46 overexpression and shRNA knockdown, F-actin staining quantification Frontiers in immunology Medium 26441997
2012 NKp46/NCR1 recognizes unknown ligands on B16 melanoma and Lewis lung carcinoma (D122) cells; NCR1 mediates direct killing of these tumor cells in vitro; in vivo, NCR1-deficient mice show enhanced spontaneous tumor metastasis in both models. Ncr1 knockout mice, spontaneous metastasis models, in vitro NK killing assays with blocking antibodies, NKp46-Fc fusion protein ligand detection Journal of immunology High 22308311
2012 oHSV infection upregulates NKp46 (NKp30 and NKp46) ligands on glioblastoma cells; NK killing of oHSV-infected glioblastoma depends on NKp30 and NKp46 NCRs; Ncr1-deficient mice show increased HSV titers and improved oHSV efficacy, demonstrating that NKp46-driven NK antiviral activity limits oncolytic virus therapy. Ncr1 knockout mice, adoptive transfer models, in vitro blocking antibody experiments, ligand upregulation analysis Nature medicine High 23178246
2013 Influenza neuraminidase (NA) cleaves sialic acid residues from NKp46, reducing its ability to recognize viral hemagglutinin; NA inhibitors (used clinically to block virus budding) also boost NKp46-mediated recognition of infected cells by preserving NKp46 sialylation. NA inhibitor treatment, sialic acid modification experiments, in vivo and in vitro influenza infection models, NKp46-HA binding assays Cell reports High 23602571
2014 Type I IFN signaling on T cells protects them from NCR1-mediated NK cell killing by suppressing NCR1 ligand expression on T cells; Ifnar1-deficient T cells upregulate NCR1 ligands and are killed by NK cells in a perforin-dependent manner; NK cell depletion rescues early expansion of Ifnar1-/- T cells during LCMV infection. Ifnar1 knockout mice, NK cell depletion experiments, LCMV infection model, NCR1 ligand expression analysis Immunity High 24909889
2014 In the absence of NKp46, GVHD is exacerbated following hematopoietic stem cell transplantation, resulting in rapid mortality from commensal bacteria infection; this is due to an altered ability of immune cells to respond to stimulation by immature dendritic cells. Ncr1 knockout mice in HSCT model, survival analysis, immune cell response assays to immature DCs Cell reports Medium 24882008
2016 NKp46 and its mouse ortholog NCR1 recognize fungal adhesins Epa1, Epa6, and Epa7 on Candida glabrata; NCR1 knockout mice fail to clear systemic C. glabrata infection in vivo; this identifies NKp46/NCR1 as a pattern recognition receptor for fungal pathogens. NCR1 knockout mice in vivo infection model, fungal adhesin ligand identification, in vitro NK killing assays Cell host & microbe High 27736647
2016 Neutrophil-derived cathepsin G (but not elastase or proteinase 3) induces time- and concentration-dependent proteolytic cleavage of NKp46 on NK cells; this cleavage impairs NKp46-mediated IFN-γ production and degranulation; cystic fibrosis patient sputa with high cathepsin G levels also cleave NKp46. Flow cytometry, Western blotting, mass spectrometry, functional NK cell assays, protease inhibitor experiments Journal of leukocyte biology High 27587403
2017 NKp46 binds to complement factor P (properdin/CFP), the only known positive regulator of the alternative complement pathway; NKp46 and group 1 NKp46+ ILCs are required for mice to survive Neisseria meningitidis infection; beneficial effects of CFP treatment for Nm infection depend on NKp46. Ligand identification (binding assays), Ncr1 knockout mice with Nm infection model, CFP treatment experiments Science immunology High 28480349
2018 NKp46 (NCR1 in mouse) signaling induces IFN-γ secretion from intratumoral NK cells, which increases fibronectin 1 (FN1) expression in tumors, alters primary tumor architecture, and decreases metastasis formation; this mechanism was visualized in vivo by reflectance confocal microscopy. Ncr1 knockout mice, IFN-γ injection in tumor-bearing mice, transgenic Ncr1 overexpression mice, reflectance confocal microscopy, FN1 expression analysis Immunity High 29329948
2018 NKG2D specifically sets the activation threshold for NCR1 signaling through a process requiring the adaptor DAP12; NKG2D expression before the immature NK cell stage increases CD3ζ expression; reduced CD3ζ in Klrk1-/- mice enhances NCR1 signal transduction, and CD3ζ deficiency results in NCR1 hyper-responsiveness. Klrk1 (NKG2D) knockout mice, DAP12-deficient mice, CD3ζ expression analysis, in vivo infection and tumor models, NCR1-specific functional assays Nature immunology High 30224819
2018 NKp46 expression on ILC1s controls TRAIL expression; in the absence of NKp46, ILC1s fail to express normal levels of TRAIL on the surface, resulting in diminished cytotoxicity toward TRAIL receptor-positive targets. Ncr1 knockout mice, TRAIL expression analysis, cytotoxicity assays against TRAIL receptor-positive targets Journal of immunology Medium 29661825
2012 RUNX3 transcription factor directly binds a RUNX recognition motif in a cis-regulatory enhancer/repressor element upstream of the NCR1 gene; interfering with RUNX proteins using dominant-negative forms decreases Ncr1 expression; RUNX3 overexpression increases NCR1 expression, establishing RUNX3 as a key transcriptional regulator of NK-specific NCR1 expression. Promoter analysis, EMSA, RUNX3 overexpression, dominant-negative RUNX constructs, reporter assays The Journal of biological chemistry High 22253448
2019 STAT3 directly binds to the promoter of NKp46 (NCR1) to regulate its transcription and expression in NK cells; HBsAg inhibits STAT3 expression and activation in NK cells, suppressing NKp46-dependent NK cell function in chronic hepatitis B. ChIP assay demonstrating STAT3 promoter binding, STAT3 knockdown, HBsAg treatment of NK cells, flow cytometry Journal of leukocyte biology Medium 31132315
2013 NKp46 engagement on malignant Sézary CD4+ T cells provides an inhibitory signal on CD3-induced proliferation; this inhibition correlates with decreased phosphorylation of the CD3ζ chain associated with NKp46 and/or TCR/CD3 complexes. mAb engagement assays, T cell proliferation assay, CD3ζ phosphorylation analysis The Journal of investigative dermatology Medium 21191411
2023 NKp46 (NCR1) recognizes externalized calreticulin (ecto-CRT) on the cell surface during ER stress as its endogenous ligand; NKp46 binds the P domain of ecto-CRT; NKp46 caps with ecto-CRT at NK immune synapses; knockout of CALR or NCR1 impairs NK killing of ER-stressed, flavivirus-infected, senescent, and ecto-CRT-expressing cancer cells; NKp46 recognition of ecto-CRT controls mouse B16 melanoma and RAS-driven lung cancers. Co-IP, structural domain analysis, CRISPR knockout of CALR and NCR1, NK immune synapse imaging, in vivo tumor models, CRT antibody blocking, GPI-anchored CRT overexpression Nature High 37020026

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 918 19084435
2008 RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature immunology 712 19029903
2001 Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 705 11234016
2008 Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nature immunology 476 19029904
1998 Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. The Journal of experimental medicine 464 9730896
2006 Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nature immunology 433 16565719
2007 Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46. Proceedings of the National Academy of Sciences of the United States of America 368 17360655
2019 Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity. Cell 359 31155232
1999 NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells. European journal of immunology 341 10359120
2011 Fate mapping analysis of lymphoid cells expressing the NKp46 cell surface receptor. Proceedings of the National Academy of Sciences of the United States of America 289 22021440
2007 The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer research 273 17875681
2010 IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. The Journal of experimental medicine 260 20142427
2013 The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway. Nature immunology 250 23455676
2010 Imbalance of NKp44(+)NKp46(-) and NKp44(-)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn's disease. Gastroenterology 199 20638936
2014 Type I interferons protect T cells against NK cell attack mediated by the activating receptor NCR1. Immunity 196 24909889
2015 Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. The Journal of experimental medicine 187 26458769
2010 IL-12 initiates tumor rejection via lymphoid tissue-inducer cells bearing the natural cytotoxicity receptor NKp46. Nature immunology 185 20935648
2003 The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46. Blood 185 14504081
2010 A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK-cell survival and development. Blood 177 21127177
2012 NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors. Nature medicine 168 23178246
2009 Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC cancer 168 19531227
2012 Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses. Science (New York, N.Y.) 162 22267813
2009 The activating receptor NKp46 is essential for the development of type 1 diabetes. Nature immunology 150 20023661
2011 Identity, regulation and in vivo function of gut NKp46+RORγt+ and NKp46+RORγt- lymphoid cells. The EMBO journal 146 21685873
2018 NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis. Immunity 144 29329948
2006 Vimentin expressed on Mycobacterium tuberculosis-infected human monocytes is involved in binding to the NKp46 receptor. Journal of immunology (Baltimore, Md. : 1950) 140 17056548
2012 Recognition and prevention of tumor metastasis by the NK receptor NKp46/NCR1. Journal of immunology (Baltimore, Md. : 1950) 137 22308311
2023 The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells. Nature 136 37020026
2011 NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut 134 22198715
1999 The murine homologue of the human NKp46, a triggering receptor involved in the induction of natural cytotoxicity. European journal of immunology 132 10092106
2009 Natural cytotoxicity receptors NKp30, NKp44 and NKp46 bind to different heparan sulfate/heparin sequences. Journal of proteome research 130 19196184
2009 Enhanced in vivo growth of lymphoma tumors in the absence of the NK-activating receptor NKp46/NCR1. Journal of immunology (Baltimore, Md. : 1950) 125 19201876
2002 The NKp46 receptor contributes to NK cell lysis of mononuclear phagocytes infected with an intracellular bacterium. Journal of immunology (Baltimore, Md. : 1950) 119 11907104
2004 Membrane-associated heparan sulfate proteoglycans are involved in the recognition of cellular targets by NKp30 and NKp46. Journal of immunology (Baltimore, Md. : 1950) 114 15294952
2019 NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer. JCI insight 113 31689241
2013 TCF-1 controls ILC2 and NKp46+RORγt+ innate lymphocyte differentiation and protection in intestinal inflammation. Journal of immunology (Baltimore, Md. : 1950) 112 24038093
2008 Critical and differential roles of NKp46- and NKp30-activating receptors expressed by uterine NK cells in early pregnancy. Journal of immunology (Baltimore, Md. : 1950) 111 18713971
2007 Natural killer cells: from CD3(-)NKp46(+) to post-genomics meta-analyses. Current opinion in immunology 108 17442558
2004 NKp46 defines a subset of bovine leukocytes with natural killer cell characteristics. European journal of immunology 108 14991596
2019 KLRG1 and NKp46 discriminate subpopulations of human CD117+CRTH2- ILCs biased toward ILC2 or ILC3. The Journal of experimental medicine 104 31201208
2010 Reduced frequencies of NKp30+NKp46+, CD161+, and NKG2D+ NK cells in acute HCV infection may predict viral clearance. Journal of hepatology 103 21168454
2018 Altered NKp30, NKp46, NKG2D, and DNAM-1 Expression on Circulating NK Cells Is Associated with Tumor Progression in Human Gastric Cancer. Journal of immunology research 101 30255106
2017 Complement factor P is a ligand for the natural killer cell-activating receptor NKp46. Science immunology 100 28480349
2006 Adenosine-mediated inhibition of cytotoxic activity and cytokine production by IL-2/NKp46-activated NK cells: involvement of protein kinase A isozyme I (PKA I). Immunologic research 100 17337770
2010 NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies. Blood 97 21030563
2012 Human NK Cells induce neutrophil apoptosis via an NKp46- and Fas-dependent mechanism. Journal of immunology (Baltimore, Md. : 1950) 95 22231698
2017 T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation. Nature immunology 94 28805812
2011 Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD. European journal of immunology 93 22105417
2009 The natural cytotoxicity receptor NKp46 is dispensable for IL-22-mediated innate intestinal immune defense against Citrobacter rodentium. Journal of immunology (Baltimore, Md. : 1950) 91 19846871
2011 Modulation of NKp30- and NKp46-mediated natural killer cell responses by poxviral hemagglutinin. PLoS pathogens 88 21901096
2012 Interleukin-15-dependent NKp46+ innate lymphoid cells control intestinal inflammation by recruiting inflammatory monocytes. Immunity 85 22705105
2023 Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123. Nature biotechnology 77 36635380
2016 NK Cell Recognition of Candida glabrata through Binding of NKp46 and NCR1 to Fungal Ligands Epa1, Epa6, and Epa7. Cell host & microbe 77 27736647
2010 Tumor immunoediting by NKp46. Journal of immunology (Baltimore, Md. : 1950) 75 20404273
2004 NCR-1 and NCR-2, the C. elegans homologs of the human Niemann-Pick type C1 disease protein, function upstream of DAF-9 in the dauer formation pathways. Development (Cambridge, England) 72 15509773
2011 Activating NK cell receptor expression/function (NKp30, NKp46, DNAM-1) during chronic viraemic HCV infection is associated with the outcome of combined treatment. European journal of immunology 69 21695691
2012 Innate immunity in multiple sclerosis white matter lesions: expression of natural cytotoxicity triggering receptor 1 (NCR1). Journal of neuroinflammation 67 22212381
2008 Human NK cells kill resting but not activated microglia via NKG2D- and NKp46-mediated recognition. Journal of immunology (Baltimore, Md. : 1950) 64 18941207
2012 Mapping of NKp46(+) Cells in Healthy Human Lymphoid and Non-Lymphoid Tissues. Frontiers in immunology 62 23181063
2006 NKp46 and NKG2D receptor expression in NK cells with CD56dim and CD56bright phenotype: regulation by histamine and reactive oxygen species. British journal of haematology 62 16371024
2004 Rat NKp46 activates natural killer cell cytotoxicity and is associated with FcepsilonRIgamma and CD3zeta. Journal of leukocyte biology 59 15356098
2011 NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human. The Journal of clinical investigation 56 21364281
2018 NK cell receptor NKG2D sets activation threshold for the NCR1 receptor early in NK cell development. Nature immunology 55 30224819
2012 NKp46 expression discriminates porcine NK cells with different functional properties. European journal of immunology 55 22539298
2011 Recognition and killing of human and murine pancreatic beta cells by the NK receptor NKp46. Journal of immunology (Baltimore, Md. : 1950) 52 21849674
2013 The paradox of NKp46+ natural killer cells: drivers of severe hepatitis C virus-induced pathology but in-vivo resistance to interferon α treatment. Gut 51 23665989
2017 Control of the HIV-1 DNA Reservoir Is Associated In Vivo and In Vitro with NKp46/NKp30 (CD335 CD337) Inducibility and Interferon Gamma Production by Transcriptionally Unique NK Cells. Journal of virology 50 28956765
2013 Neuraminidase-mediated, NKp46-dependent immune-evasion mechanism of influenza viruses. Cell reports 50 23602571
2012 Elucidating the mechanisms of influenza virus recognition by Ncr1. PloS one 48 22615821
2015 NKp46 Clusters at the Immune Synapse and Regulates NK Cell Polarization. Frontiers in immunology 47 26441997
2006 Bovine CD2-/NKp46+ cells are fully functional natural killer cells with a high activation status. BMC immunology 47 16643649
2001 NKp46. The international journal of biochemistry & cell biology 47 11606250
2018 NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study. Gut 43 30448772
2016 Phenotypic and Functional Plasticity of Murine Intestinal NKp46+ Group 3 Innate Lymphoid Cells. Journal of immunology (Baltimore, Md. : 1950) 41 27183613
2022 The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut. The Journal of experimental medicine 40 35024767
2009 Proteasome inhibition induces apoptosis in primary human natural killer cells and suppresses NKp46-mediated cytotoxicity. Haematologica 39 19229052
2007 Expression of ligands to NKp46 in benign and malignant melanocytes. The Journal of investigative dermatology 39 17972960
2005 Characterization of the heparin/heparan sulfate binding site of the natural cytotoxicity receptor NKp46. Biochemistry 39 16262248
2015 Lysis of HIV-1-infected autologous CD4+ primary T cells by interferon-alpha-activated NK cells requires NKp46 and NKG2D. AIDS (London, England) 38 26372382
2012 Role of runt-related transcription factor 3 (RUNX3) in transcription regulation of natural cytotoxicity receptor 1 (NCR1/NKp46), an activating natural killer (NK) cell receptor. The Journal of biological chemistry 37 22253448
2016 NCR1 Expression Identifies Canine Natural Killer Cell Subsets with Phenotypic Similarity to Human Natural Killer Cells. Frontiers in immunology 36 27933061
2014 Balance between activating NKG2D, DNAM-1, NKp44 and NKp46 and inhibitory CD94/NKG2A receptors determine natural killer degranulation towards rheumatoid arthritis synovial fibroblasts. Immunology 36 24673109
2013 Expression of the activating receptor, NKp46 (CD335), in human natural killer and T-cell neoplasia. American journal of clinical pathology 36 24225754
2014 NK cell receptor NKp46 regulates graft-versus-host disease. Cell reports 35 24882008
2010 Expression and function of the natural cytotoxicity receptor NKp46 on circulating malignant CD4+ T lymphocytes of Sézary syndrome patients. The Journal of investigative dermatology 35 21191411
2018 NKp46 Calibrates Tumoricidal Potential of Type 1 Innate Lymphocytes by Regulating TRAIL Expression. Journal of immunology (Baltimore, Md. : 1950) 33 29661825
2011 NKp46 defines ovine cells that have characteristics corresponding to NK cells. Veterinary research 33 21345198
2018 Circulating NKp46+ Natural Killer cells have a potential regulatory property and predict distinct survival in Non-Small Cell Lung Cancer. Oncoimmunology 32 30713781
2014 Conditional ablation of NKp46+ cells using a novel Ncr1(greenCre) mouse strain: NK cells are essential for protection against pulmonary B16 metastases. European journal of immunology 32 25142413
2012 CD158k/KIR3DL2 and NKp46 are frequently expressed in transformed mycosis fungoides. Experimental dermatology 32 22621189
2016 Neutrophils can disarm NK cell response through cleavage of NKp46. Journal of leukocyte biology 31 27587403
2013 Anti-HIV antibody-dependent activation of NK cells impairs NKp46 expression. Journal of immunology (Baltimore, Md. : 1950) 31 24319263
2020 Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy. Cells 29 32204481
2014 An NCR1-based chimeric receptor endows T-cells with multiple anti-tumor specificities. Oncotarget 29 25431955
2008 Bovine WC1(-) gammadeltaT cells incubated with IL-15 express the natural cytotoxicity receptor CD335 (NKp46) and produce IFN-gamma in response to exogenous IL-12 and IL-18. Developmental and comparative immunology 29 18329100
2018 HIF-1α induces immune escape of prostate cancer by regulating NCR1/NKp46 signaling through miR-224. Biochemical and biophysical research communications 28 29885835
2011 Lymphotoxin-β receptor-independent development of intestinal IL-22-producing NKp46+ innate lymphoid cells. European journal of immunology 27 21341264
2019 STAT3 directly regulates NKp46 transcription in NK cells of HBeAg-negative CHB patients. Journal of leukocyte biology 26 31132315
2018 MiR-544 promotes immune escape through downregulation of NCR1/NKp46 via targeting RUNX3 in liver cancer. Cancer cell international 26 29636640
2013 NKp46 regulates allergic responses. European journal of immunology 26 23878025