Affinage

Showing NCR1 — NKP46 is a alias.

NCR1

Natural cytotoxicity triggering receptor 1 · UniProt O76036

Length
304 aa
Mass
34.5 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NCR1 (NKp46/CD335) is a principal activating receptor of natural killer cells and group 1 innate lymphoid cells that triggers natural cytotoxicity and cytokine secretion against virally infected, tumorigenic, and stressed cells (PMID:10359120, PMID:17360655). Receptor engagement associates with the ITAM-bearing adaptors CD3ζ and FcεRIγ and activates PI3K/Akt signaling, driving calcium mobilization, granule polarization, and target lysis (PMID:15356098, PMID:11385609, PMID:18713971); at the immune synapse NKp46 forms microclusters that recruit F-actin and direct lytic granules toward the target cell (PMID:26441997). NKp46 recognizes a diverse ligand repertoire: influenza, Sendai, and poxviral hemagglutinins via sialic acid and O-/N-glycosylation on the receptor itself (PMID:14504081, PMID:21901096, PMID:22615821), heparan sulfate structures and unknown ligands on tumor cells (PMID:19196184, PMID:22308311, PMID:19201876), ligands on hepatic stellate cells and pancreatic β cells (PMID:22198715, PMID:21849674, PMID:20023661), fungal Epa adhesins of C. glabrata (PMID:27736647), complement factor P (PMID:28480349), and the endogenous danger ligand externalized calreticulin, which it binds via the CRT P domain on ER-stressed, senescent, infected, and dying cells (PMID:37020026). Through these recognition events NCR1 is required in vivo for control of influenza infection, type 1 diabetes, liver fibrosis, fungal infection, and tumor metastasis, the latter in part through IFN-γ-driven fibronectin remodeling of tumor architecture (PMID:16565719, PMID:20023661, PMID:22198715, PMID:27736647, PMID:29329948), while also restraining graft-versus-host disease and shaping adaptive T cell responses through perforin-dependent killing of type-I-IFN-unprotected T cells (PMID:24882008, PMID:24909889). Receptor abundance and signaling are tightly calibrated transcriptionally by RUNX3 (PMID:22253448), developmentally by an NKG2D–DAP12–CD3ζ axis that sets the NCR1 activation threshold and controls ILC1 TRAIL expression (PMID:30224819, PMID:29661825), and post-translationally by influenza neuraminidase desialylation and neutrophil cathepsin G cleavage as immune-evasion mechanisms (PMID:23602571, PMID:27587403).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1999 High

    Established NKp46 as the principal activating receptor responsible for natural cytotoxicity against HLA-class-I-deficient targets, defining its core cellular role.

    Evidence mAb masking and chromium-release cytotoxicity across NK clones

    PMID:10359120

    Open questions at the time
    • Did not identify the signaling adaptor or downstream pathway
    • Endogenous ligand unidentified
  2. 2001 Medium

    Connected NKp46 ligation to an intracellular signaling pathway by showing it activates PI3K/Akt required for target lysis.

    Evidence Redirected killing with PI3K inhibitors and Akt activation readout

    PMID:11385609

    Open questions at the time
    • Pharmacological inhibitors only
    • Did not define receptor-proximal adaptor coupling to PI3K
  3. 2003 High

    Identified the first molecular ligands (viral hemagglutinins) and showed recognition depends on α2,6-sialic acid and glycosylation on the receptor itself, mapping interactions to the membrane-proximal domain and Thr225.

    Evidence Direct binding assays with site-directed mutagenesis and sialic acid modification

    PMID:14504081

    Open questions at the time
    • Tumor ligand remained unknown
    • Endogenous self-ligand not defined
  4. 2004 Medium

    Defined the signaling mechanism by demonstrating association with the ITAM-bearing adaptors CD3ζ and FcεRIγ, analogous to CD16.

    Evidence Reciprocal immunoprecipitation and redirected lysis in rat NKp46

    PMID:15356098

    Open questions at the time
    • Rat ortholog; human stoichiometry not quantified
    • Link from ITAM to PI3K not traced
  5. 2006 High

    Provided in vivo proof that NCR1 is essential for host defense, with knockout mice dying of influenza infection.

    Evidence Ncr1(gfp/gfp) knockout mice in lethal influenza model across two strains

    PMID:16565719

    Open questions at the time
    • Did not establish which viral ligand mediates protection in vivo
    • NK effector mechanism not dissected in vivo
  6. 2006 Medium

    Showed receptor surface levels are environmentally tunable, as the IDO metabolite L-kynurenine and adenosine/A2A-cAMP-PKA I signaling suppress NKp46 expression and function.

    Evidence Flow cytometry, RT-PCR, crosslinking assays with receptor and PKA-subunit pharmacology

    PMID:16902152 PMID:17337770

    Open questions at the time
    • Mechanism of transcriptional suppression unresolved
    • Single-lab pharmacological dissection
  7. 2009 High

    Extended NCR1's in vivo roles to autoimmunity, tumor surveillance, and tissue fibrosis by linking it to β-cell killing in diabetes, lymphoma rejection, and hepatic stellate cell killing.

    Evidence Ncr1 knockout disease models (streptozotocin/NOD diabetes, PD1.6 lymphoma, CCl4 fibrosis) with NKp46-Fc ligand staining

    PMID:19201876 PMID:20023661 PMID:22198715

    Open questions at the time
    • Endogenous ligands on β cells, lymphoma, and stellate cells remained molecularly unidentified
  8. 2009 Medium

    Characterized heparan sulfate/heparin as a class of tumor-relevant NKp46 ligands and quantified binding.

    Evidence HS oligosaccharide microarray, surface plasmon resonance, and NK activation

    PMID:19196184

    Open questions at the time
    • Affinities lower than NKp30/NKp44; physiological relevance on specific tumors not fully defined
  9. 2011 High

    Refined ligand-recognition determinants by mapping β-cell ligand binding to the membrane-proximal/stalk region and specific glycosylated residues Thr125 and Asn216.

    Evidence NKp46-Fc binding with glycosylation-site mutagenesis and killing assays in human and mouse cells

    PMID:21849674

    Open questions at the time
    • β-cell ligand identity still unknown
    • Mechanistic basis for glycan dependence unresolved
  10. 2012 High

    Revealed a self-limiting regulatory function: an Ncr1 loss-of-function mutation produces hyperresponsive NK cells, with NKp46 promoting inhibitory Helios expression.

    Evidence ENU mutagenesis, whole-genome sequencing, viral challenge, and in vivo NKp46 blockade

    PMID:22267813

    Open questions at the time
    • Pathway linking NKp46 to Helios transcription not defined
  11. 2012 Medium

    Defined the synaptic and transcriptional basis of NKp46 action by linking it to F-actin recruitment and lytic granule polarization, and to RUNX3-driven NK-specific transcription.

    Evidence Live imaging with NKp46 gain/loss-of-function; reporter assays and EMSA with RUNX3 manipulation

    PMID:22253448 PMID:26441997

    Open questions at the time
    • Direct molecular link from microclusters to actin machinery not detailed
    • Single-lab transcriptional data
  12. 2012 High

    Established NCR1's role in tumor metastasis control and showed it limits oncolytic virotherapy by recognizing ligands on infected/tumor cells.

    Evidence Ncr1 knockout spontaneous-metastasis and oHSV glioblastoma models with NKp46-Fc staining

    PMID:22308311 PMID:23178246

    Open questions at the time
    • Tumor and oHSV-induced ligands not molecularly identified
  13. 2013 High

    Uncovered an influenza immune-evasion mechanism whereby viral neuraminidase desialylates NKp46 to abolish HA recognition, reversible by clinical NA inhibitors.

    Evidence NA inhibitor experiments in vitro and in vivo with sialic acid and recognition assays

    PMID:22615821 PMID:23602571

    Open questions at the time
    • Precise N-glycosylated residues mediating HA recognition not fully identified
  14. 2014 High

    Defined an immunoregulatory role in adaptive immunity: NCR1 mediates perforin-dependent killing of T cells lacking type I IFN protection.

    Evidence Ifnar1(-/-) mice with NK depletion epistasis and NCR1 blockade in LCMV infection

    PMID:24909889

    Open questions at the time
    • NCR1 ligand upregulated on IFN-unprotected T cells not identified
  15. 2016 High

    Identified the first defined microbial protein ligands (C. glabrata Epa1/6/7 adhesins) and established NCR1 in antifungal defense.

    Evidence NCR1 knockout C. glabrata infection models with defined adhesin binding

    PMID:27736647

    Open questions at the time
    • Receptor binding interface for Epa adhesins not structurally mapped
  16. 2016 Medium

    Demonstrated a host protease evasion route in which neutrophil cathepsin G cleaves NKp46 and impairs NK function, relevant to cystic fibrosis.

    Evidence Protease specificity by mass spectrometry, Western blot, and CF sputum functional assays

    PMID:27587403

    Open questions at the time
    • Cleavage site and protease-resistant variants not defined
    • Single lab
  17. 2017 High

    Identified a soluble plasma ligand, complement factor P (properdin), linking NKp46+ ILCs to antibacterial survival.

    Evidence NKp46-CFP binding assay with knockout mice and CFP-rescue in Neisseria infection

    PMID:28480349

    Open questions at the time
    • Functional consequence of CFP binding for downstream signaling not detailed
  18. 2018 High

    Established a downstream effector mechanism for metastasis control: NKp46-driven IFN-γ increases tumor fibronectin and remodels tumor architecture.

    Evidence In vivo confocal imaging, Ncr1 knockout/transgenic overexpression, IFN-γ injection rescue

    PMID:29329948

    Open questions at the time
    • Triggering ligand on the relevant tumors not identified
  19. 2018 High

    Defined developmental calibration of the receptor: NKG2D sets the NCR1 activation threshold via DAP12-dependent CD3ζ levels, and NKp46 controls ILC1 TRAIL expression.

    Evidence Klrk1(-/-) and DAP12-deficient mice with CD3ζ analysis and MCMV/tumor challenge; TRAIL/cytotoxicity in NKp46-deficient ILC1s

    PMID:29661825 PMID:30224819

    Open questions at the time
    • Molecular basis of how CD3ζ abundance tunes NCR1 signal strength not fully resolved
  20. 2018 Low

    Implicated microRNA circuits (miR-224 via HIF-1α, miR-544 via RUNX3) in tumor-driven suppression of NCR1 expression.

    Evidence miRNA mimics/inhibitors with luciferase reporters and NK cytotoxicity assays

    PMID:29636640 PMID:29885835

    Open questions at the time
    • Single-lab reporter/overexpression studies with limited mechanistic follow-up
    • In vivo physiological relevance of these miRNA axes not established
  21. 2023 High

    Identified the principal endogenous danger ligand: externalized calreticulin, bound via its P domain on ER-stressed, senescent, infected, and dying cells, unifying NCR1's recognition of stressed self.

    Evidence Co-IP, binding assays, CALR KO/KD, GPI-anchored CRT ectopic expression, synapse imaging, and NCR1-deficient tumor/ZIKV models

    PMID:37020026

    Open questions at the time
    • Relationship between ecto-CRT and the many previously reported unidentified cellular ligands not reconciled
    • Structural detail of the NKp46–CRT P-domain interface not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identities of multiple reported endogenous ligands (on tumor cells, hepatic stellate cells, β cells, and IFN-unprotected T cells) and how they relate to ecto-CRT remain unresolved, as does the structural basis for NCR1's glycan-dependent multi-ligand recognition.
  • Several disease-relevant ligands remain molecularly uncharacterized
  • No high-resolution structure of NCR1 with an endogenous ligand
  • Mechanism integrating diverse ligand inputs into a single ITAM signal undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 3 GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3
Partners
CALRCD247CFPDAP12FCER1GNKG2DRUNX3

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Surface density of NKp46 on NK clones directly correlates with natural cytotoxicity against HLA-class I-unprotected target cells; antibody-mediated masking of NKp46 inhibits cytolysis, establishing NKp46 as a principal activating receptor mediating natural cytotoxicity. Monoclonal antibody masking assay, NK clone cytotoxicity assay (chromium release) European journal of immunology High 10359120
2001 NKp46 ligation on NK cells activates phosphatidylinositol 3-kinase (PI3K), and PI3K inhibitors (LY294002, wortmannin) block NK cell-mediated lysis of autologous antigen-presenting cells and reduce Akt/PKB activation triggered by NKp30 or NKp46 engagement. Redirected killing assay, PI3K inhibitor treatment, Akt/PKB activation assay European journal of immunology Medium 11385609
2002 NKp46 receptor expression (mRNA) is upregulated on NK cells in response to M. tuberculosis-infected monocytes, and antibody-mediated masking of NKp46 markedly inhibits NK lysis of infected monocytes, establishing NKp46 as a mediator of NK killing of intracellularly bacterium-infected cells. RT-PCR for NKp46 mRNA, antibody-blocking cytotoxicity assay Journal of immunology Medium 11907104
2003 NKp46 directly binds influenza and Sendai virus hemagglutinins in a sialic acid-dependent manner; the interaction is primarily mediated via alpha2,6-linked sialic acid carried on NKp46. Recognition of target cells (both viral and tumor) is confined to the membrane-proximal domain of NKp46. A highly conserved O-glycosylated residue, Thr225, plays a dual critical role in NKp46 interactions with both viral hemagglutinins and unknown tumor ligands through different mechanisms. Direct binding assay, site-directed mutagenesis of NKp46 residues, sialic acid modification experiments, cytotoxicity assay Blood High 14504081
2004 Rat NKp46 is an activating NK cell receptor; immunoprecipitation demonstrated that rat NKp46 associates with the ITAM-bearing adaptor proteins CD3ζ and FcεRIγ, establishing its signaling mechanism analogous to CD16. Immunoprecipitation/Western blot, redirected lysis assay, flow cytometry Journal of leukocyte biology Medium 15356098
2006 L-kynurenine, a tryptophan catabolite produced by IDO, prevents cytokine-mediated up-regulation of NKp46 surface expression (at both transcriptional and protein levels) and impairs NK cell killing of targets recognized via NKp46; this effect is specific to NKp46 and NKG2D but not NKp30 or CD16, and is reversible upon washing. Flow cytometry for receptor expression, NK cytotoxicity assay, RT-PCR for mRNA levels Blood Medium 16902152
2006 NCR1 (mouse ortholog of NKp46) is required for in vivo control of influenza virus infection; Ncr1-deficient mice (both 129/Sv and C57BL/6) succumb to lethal influenza infection, and NK cells accumulate at the infection site as tracked by GFP reporter. Ncr1(gfp/gfp) knockout mouse, influenza infection survival model, GFP-based NK cell tracking Nature immunology High 16565719
2006 Adenosine suppresses NKp46-receptor crosslinking-mediated NK cell cytotoxic activity and cytokine/chemokine production via A2A adenosine receptor signaling, increased cAMP, and activation of PKA isozyme I (PKA I), but not PKA II. NKp46 receptor crosslinking assay, adenosine receptor pharmacology, PKA subunit blockade Immunologic research Medium 17337770
2007 NKp46 recognizes influenza hemagglutinin on infected dendritic cells; antibody blockade of NKp46 (along with NKG2D) inhibits CD69 upregulation and IFN-γ production (but not enhanced cytolysis) of resting NK cells activated by influenza-infected DCs. Antibody-blocking assay, NK cell activation readouts (CD69, IFN-γ, cytolysis), influenza-infected DC co-culture Journal of immunology Medium 17312110
2007 NKp46/CD335 is expressed by NK cells across all mouse strains and multiple monkey species; mouse NKp46 triggers NK cell effector function in a redirected lysis assay; NKp46 expression is detected from the immature CD122+NK1.1+DX5- stage onward; human NKp46 promoter drives NK-cell-selective expression in vitro and in vivo in transgenic mice. Flow cytometry across species, redirected lysis assay, transgenic mice with NKp46 promoter-driven EGFP and diphtheria toxin receptor Proceedings of the National Academy of Sciences High 17360655
2008 In human decidual NK (dNK) cells, antibody-mediated engagement of NKp46 (but not NKp30) induces intracellular calcium mobilization, perforin polarization, granule exocytosis, and efficient target cell lysis; NKp46-mediated cytotoxicity is co-activated by CD2 but blocked by NKG2A co-engagement. Conversely, NKp30 (but not NKp46) engagement triggers IFN-γ, TNF-α, and chemokine production in dNK cells. mAb-specific receptor engagement, calcium mobilization assay, perforin polarization, granule exocytosis assay, cytotoxicity assay, cytokine measurement Journal of immunology High 18713971
2009 NCR1 (mouse NKp46 ortholog) binds to NKp46 ligands expressed on hepatic stellate cells (HSC); NCR1-deficient mice develop enhanced liver fibrosis in a carbon tetrachloride model; murine and human HSC are killed in an NKp46/NCR1-dependent manner as shown by NKp46-Fc fusion protein binding and antibody-blocking cytotoxicity assays. NCR1/NKp46-Fc fusion protein staining, Ncr1(gfp/gfp) knockout mouse (CCl4 fibrosis model), NK killing assay with antibody blocking Gut High 22198715
2009 NKp46 recognizes specific heparan sulfate/heparin sequences on cancer cells; NKp46 binds highly charged HS/heparin structures, with binding affinities approximately one order of magnitude lower than NKp30 and NKp44; HS/heparin binding to NKp46 is relevant for tumor cell binding and NK cell activation. Microarray with heparan sulfate oligosaccharide library, surface plasmon resonance, NK cell activation assay Journal of proteome research Medium 19196184
2009 NKp46 is required for in vivo development of type 1 diabetes; NKp46 recognizes an unknown ligand on mouse and human pancreatic β cells, and NKp46 engagement by β cells leads to NK cell degranulation. NCR1-deficient mice show less streptozotocin-induced diabetes, and soluble NKp46 protein injection into NOD mice during early insulitis prevents diabetes development. Ncr1(gfp/gfp) knockout mouse (streptozotocin diabetes model), NOD mouse model with soluble NKp46 injection, NK degranulation assay Nature immunology High 20023661
2009 NCR1 is required for in vivo eradication of PD1.6 lymphoma cells; a cell reporter assay identified a NCR1 ligand on PD1.6 lymphoma cells; in Ncr1(gfp/gfp) knockout mice, PD1.6 lymphoma grows progressively whereas wild-type mice reject tumors; PD1.6 cells are less killed in vitro and in vivo in the absence of NKp46/NCR1. Cell reporter assay for ligand detection, Ncr1(gfp/gfp) knockout mouse tumor model, in vitro and in vivo NK killing assay Journal of immunology High 19201876
2011 In human NK cells, NKp46 engagement induces neutrophil apoptosis in a cell-contact-dependent and caspase-dependent manner through the Fas pathway; antibody blockade of NKp46 (along with Fas pathway inhibition) inhibits this NK-induced neutrophil apoptosis. NK-neutrophil co-culture, antibody blocking of NKp46, caspase activation assay, Fas pathway analysis Journal of immunology Medium 22231698
2011 Human and murine pancreatic β cells express an unknown NKp46 ligand and are killed in an NKp46-dependent manner; recognition is confined to the membrane-proximal domain and stalk region of NKp46; glycosylated residues Thr125 and Asn216 on NKp46 are critical for β cell ligand recognition. NKp46-Fc fusion protein binding, site-directed mutagenesis of NKp46 glycosylation sites, NK killing assay with antibody blocking, flow cytometry Journal of immunology High 21849674
2012 NKp46 forms microclusters at the immune synapse between NK cells and target cells; overexpression of human NKp46 increases F-actin accumulation at the immune synapse, and 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, F-actin staining at immune synapse, NKp46 overexpression and knockdown, lytic granule polarization assay Frontiers in immunology Medium 26441997
2012 A loss-of-function mutation in the Ncr1 gene (identified by N-ethyl-N-nitrosourea mutagenesis and whole-genome sequencing) results in hyperresponsive NK cells with increased antiviral resistance; NKp46 down-regulates NK cell activity by promoting Helios transcription factor expression in NK cells; NKp46 blockade in vivo enhances NK cell reactivity. ENU mutagenesis screen, whole-genome sequencing, Ncr1 loss-of-function mutant mice, viral infection models, Helios expression analysis, in vivo NKp46 blockade Science High 22267813
2012 NKp46 and NKp30 on NK cells are required for NK-mediated killing of oHSV-infected glioblastoma cells, as their ligands are upregulated on infected cells; in Ncr1(-/-) mice and an Ncr1(-/-) NK cell adoptive transfer model, HSV titers and oHSV efficacy are increased, demonstrating that NCR1-mediated NK cell activation limits oncolytic virotherapy. Ncr1(-/-) mouse, antibody blocking of NKp46/NKp30, NK cytotoxicity assay, adoptive transfer model, HSV titer measurement Nature medicine High 23178246
2012 NKp46/NCR1 is directly involved in killing of B16 melanoma and Lewis lung carcinoma (D122) cells; an unknown ligand for NKp46/NCR1 is expressed on these tumor cells including those generated in vivo; NCR1-deficient mice show impaired control of B16 and D122 metastasis in spontaneous metastasis models. Ncr1(gfp/gfp) knockout mouse, NKp46-Fc fusion protein staining, spontaneous metastasis models, NK killing assay Journal of immunology High 22308311
2012 RUNX3 transcription factor directly regulates NCR1/NKp46 expression; two cis-regulatory elements near the NCR1 gene act as essential promoter and tissue-dependent enhancer/repressor; the enhancer/repressor contains a RUNX recognition motif that preferentially binds RUNX3; dominant-negative RUNX interference decreases Ncr1 expression, and RUNX3 overexpression increases it. Reporter assay, dominant-negative RUNX expression, RUNX3 overexpression, EMSA/binding to RUNX motif, mRNA quantification Journal of biological chemistry Medium 22253448
2013 Influenza neuraminidase (NA) removes sialic acid residues from NKp46, thereby reducing NKp46 recognition of viral hemagglutinin (HA) and enabling influenza immune evasion; NA inhibitors (used clinically) restore NKp46 recognition by blocking this sialic acid removal; this mechanism was validated in vitro and in vivo. NA inhibitor experiments (in vitro and in vivo), sialic acid analysis, NKp46-HA recognition assay, influenza infection model Cell reports High 23602571
2013 Ncr1 recognizes influenza virus in a sialic acid-dependent manner; N-glycosylation is important for Ncr1 binding to viral hemagglutinin, but none of the predicted N-glycosylated residues are individually essential, indicating other unidentified N-glycosylated residues mediate recognition; N-glycosylation plays little role in Ncr1 recognition of mouse tumor cell lines. Mutagenesis of predicted N-glycosylation sites, sialic acid-dependent binding assay, influenza infection of Ncr1 knockout mice PLoS one Medium 22615821
2014 Type I IFN signaling directly on T cells protects them from NCR1-mediated NK cell killing; Ifnar1(-/-) T cells exhibit elevated NCR1 ligand expression upon LCMV infection, rendering them targets for NCR1-dependent NK cell attack; NK cell depletion fully restores early expansion of Ifnar1(-/-) T cells, and NCR1 mediates the perforin-dependent killing. Ifnar1(-/-) mice, NK cell depletion, NCR1-blocking experiments, LCMV infection model, NCR1 ligand expression assay Immunity High 24909889
2014 NKp46-deficient mice show exacerbated graft-versus-host disease (GVHD) with rapid mortality from commensal bacterial infection after HSCT; the exacerbated GVHD results from altered immune cell responses to stimulation by immature dendritic cells in the absence of NKp46. Ncr1(gfp/gfp) knockout mouse, HSCT model, GVHD assessment, bacterial infection analysis, DC stimulation assay Cell reports Medium 24882008
2016 NKp46 and its mouse ortholog NCR1 directly recognize C. glabrata adhesins Epa1, Epa6, and Epa7 as fungal ligands; NCR1-knockout mice show impaired control of C. glabrata infection in vitro and in vivo, and clearance of systemic infections depends on Epa1/6/7 recognition by NCR1. NCR1 knockout mouse (in vitro/in vivo C. glabrata infection), receptor-ligand binding with defined fungal adhesins, fungal infection survival assay Cell host & microbe High 27736647
2016 Neutrophil-derived cathepsin G (but not elastase or proteinase 3) cleaves NKp46 on NK cells in a time- and concentration-dependent manner, severely impairing NKp46-mediated IFN-γ production and NK cell degranulation; cystic fibrosis patient sputa (high in cathepsin G) also downregulate NKp46 on NK cells. Flow cytometry, Western blot, mass spectrometry, NK cell functional assay, CF patient sputum treatment Journal of leukocyte biology Medium 27587403
2017 NKp46 binds complement factor P (CFP/properdin), a soluble plasma glycoprotein; NKp46+ group 1 ILCs are required for survival of Neisseria meningitidis infection in mice, and the beneficial effects of CFP treatment in Nm infection are dependent on NKp46 and NKp46+ ILCs. Binding assay (NKp46-CFP interaction), NKp46/NCR1-deficient mice, Nm infection survival model, CFP treatment experiments Science immunology High 28480349
2018 NKp46 signaling (via human NKp46 and mouse Ncr1) induces IFN-γ secretion from intratumoral NK cells; NKp46/Ncr1-mediated IFN-γ production leads to increased expression of fibronectin 1 (FN1) in tumors, altering primary tumor architecture and decreasing metastasis formation; IFN-γ injection or transgenic Ncr1 overexpression in mice reduces metastasis. Reflectance confocal microscopy (in vivo imaging), Ncr1 knockout mouse, IFN-γ injection, Ncr1 transgenic overexpression, FN1 expression analysis Immunity High 29329948
2018 NKG2D specifically sets the activation threshold for NCR1 (NKp46) through a process requiring the adaptor DAP12; NKG2D engagement before the immature NK cell stage increases CD3ζ expression, and reduced CD3ζ in Klrk1(-/-) (NKG2D-deficient) mice is associated with enhanced NCR1 signal transduction; CD3ζ deficiency results in hyper-responsiveness to NCR1 stimulation. Klrk1(-/-) mouse, DAP12-deficient mouse, CD3ζ expression analysis, in vitro NCR1 stimulation, MCMV and tumor challenge models Nature immunology High 30224819
2018 NKp46 controls TRAIL expression on ILC1s; in NKp46-deficient mice, ILC1s fail to express normal TRAIL surface levels, resulting in diminished cytotoxicity toward TRAIL receptor-positive targets. NKp46-deficient mouse, TRAIL expression analysis on ILC1s, cytotoxicity assay against TRAIL receptor-positive targets Journal of immunology Medium 29661825
2011 Poxviral hemagglutinin (HA) from vaccinia virus and ectromelia virus acts as a ligand for NKp46 (and NKp30); poxviral HA on infected cell surfaces or as soluble protein stimulates NKp46-triggered activation while blocking NKp30 activation, demonstrating differential receptor-ligand effects; this was validated using NK cells with selectively silenced NCR expression and NCR-CD3ζ reporter cells. NCR-CD3ζ reporter cell assay, NCR-specific siRNA silencing, recombinant soluble HA, NK cell activation assay PLoS pathogens Medium 21901096
2023 NKp46 recognizes externalized calreticulin (ecto-CRT) on the cell surface as its endogenous ligand; ecto-CRT translocates from the ER to the cell membrane during ER stress (hallmark of chemotherapy-induced immunogenic cell death, flavivirus infection, and senescence); NKp46 specifically binds the P domain of ecto-CRT and caps with ecto-CRT at NK immune synapses; NCR1-deficient human and mouse NK cells are impaired in killing of ZIKV-infected, ER-stressed, senescent, and ecto-CRT-expressing cancer cells; NKp46 recognition of ecto-CRT controls B16 melanoma and RAS-driven lung cancers in vivo. Co-immunoprecipitation, NKp46-ecto-CRT binding assay, CALR knockout/knockdown, GPI-anchored CRT ectopic expression, NK immune synapse imaging, NCR1-deficient mouse tumor models, ZIKV infection model Nature High 37020026
2018 MiR-224 overexpression in NK cells reduces NCR1/NKp46 expression; HIF-1α increases miR-224 levels to suppress NCR1, thereby inhibiting NK cell killing of prostate cancer; dual luciferase reporter assay confirmed miR-224 directly targets the NCR1 3'UTR. miRNA overexpression, dual luciferase reporter assay, flow cytometry, NK cytotoxicity assay Biochemical and biophysical research communications Low 29885835
2018 MiR-544 directly targets RUNX3 and negatively regulates NCR1/NKp46 in NK cells; miR-544 overexpression inhibits NK cytotoxicity by downregulating IFN-γ and reducing NCR1, promoting immune escape of liver cancer cells in vivo and in vitro. miRNA mimic/inhibitor transfection, qRT-PCR, Western blot, flow cytometry, NK cytotoxicity assay, mouse liver cancer model Cancer cell international Low 29636640
2010 NKp46 ligation on NK cells in Sézary syndrome malignant CD4+ T lymphocytes delivers an inhibitory signal suppressing CD3-induced proliferation; this inhibition correlates with decreased phosphorylation of the CD3ζ chain associated with NKp46 and/or the TCR/CD3 complex. mAb-specific NKp46 engagement, proliferation assay, CD3ζ phosphorylation analysis Journal of investigative dermatology Low 21191411

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nature immunology 479 19029904
2006 Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nature immunology 435 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 369 17360655
2019 Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity. Cell 367 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
2006 The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood 332 16902152
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 291 22021440
2007 The requirement for DNAM-1, NKG2D, and NKp46 in the natural killer cell-mediated killing of myeloma cells. Cancer research 275 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 261 20142427
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 198 24909889
2015 Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. The Journal of experimental medicine 188 26458769
2003 The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46. Blood 187 14504081
2010 A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK-cell survival and development. Blood 178 21127177
2009 Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions. BMC cancer 171 19531227
2012 NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors. Nature medicine 168 23178246
2012 Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses. Science (New York, N.Y.) 162 22267813
2007 NKp46 and NKG2D recognition of infected dendritic cells is necessary for NK cell activation in the human response to influenza infection. Journal of immunology (Baltimore, Md. : 1950) 154 17312110
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 147 21685873
2023 The NK cell receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells. Nature 146 37020026
2018 NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis. Immunity 146 29329948
2012 Recognition and prevention of tumor metastasis by the NK receptor NKp46/NCR1. Journal of immunology (Baltimore, Md. : 1950) 137 22308311
2011 NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut 137 22198715
2009 Natural cytotoxicity receptors NKp30, NKp44 and NKp46 bind to different heparan sulfate/heparin sequences. Journal of proteome research 132 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
2016 NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology (Baltimore, Md.) 123 26662852
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
2019 NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer. JCI insight 116 31689241
2013 TCF-1 controls ILC2 and NKp46+RORγt+ innate lymphocyte differentiation and protection in intestinal inflammation. Journal of immunology (Baltimore, Md. : 1950) 115 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
2001 NK cell-mediated lysis of autologous antigen-presenting cells is triggered by the engagement of the phosphatidylinositol 3-kinase upon ligation of the natural cytotoxicity receptors NKp30 and NKp46. European journal of immunology 110 11385609
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
2010 Reduced frequencies of NKp30+NKp46+, CD161+, and NKG2D+ NK cells in acute HCV infection may predict viral clearance. Journal of hepatology 106 21168454
2019 KLRG1 and NKp46 discriminate subpopulations of human CD117+CRTH2- ILCs biased toward ILC2 or ILC3. The Journal of experimental medicine 104 31201208
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 104 30255106
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 103 17337770
2017 Complement factor P is a ligand for the natural killer cell-activating receptor NKp46. Science immunology 102 28480349
2008 Regulatory role of NKp44, NKp46, DNAM-1 and NKG2D receptors in the interaction between NK cells and trophoblast cells. Evidence for divergent functional profiles of decidual versus peripheral NK cells. International immunology 99 18815119
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 97 22105417
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
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 89 21901096
2023 Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123. Nature biotechnology 83 36635380
2016 NK Cell Recognition of Candida glabrata through Binding of NKp46 and NCR1 to Fungal Ligands Epa1, Epa6, and Epa7. Cell host & microbe 78 27736647
2010 Tumor immunoediting by NKp46. Journal of immunology (Baltimore, Md. : 1950) 75 20404273
2012 Innate immunity in multiple sclerosis white matter lesions: expression of natural cytotoxicity triggering receptor 1 (NCR1). Journal of neuroinflammation 69 22212381
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
2008 Human NK cells kill resting but not activated microglia via NKG2D- and NKp46-mediated recognition. Journal of immunology (Baltimore, Md. : 1950) 65 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
2001 Identification, molecular cloning and functional characterization of NKp46 and NKp30 natural cytotoxicity receptors in Macaca fascicularis NK cells. European journal of immunology 58 11745374
2018 NK cell receptor NKG2D sets activation threshold for the NCR1 receptor early in NK cell development. Nature immunology 56 30224819
2011 NKp46 identifies an NKT cell subset susceptible to leukemic transformation in mouse and human. The Journal of clinical investigation 56 21364281
2019 Indoleamine-2,3-Dioxygenase in Thyroid Cancer Cells Suppresses Natural Killer Cell Function by Inhibiting NKG2D and NKp46 Expression via STAT Signaling Pathways. Journal of clinical medicine 55 31212870
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
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
2001 NKp46. The international journal of biochemistry & cell biology 48 11606250
2015 NKp46 Clusters at the Immune Synapse and Regulates NK Cell Polarization. Frontiers in immunology 47 26441997
2018 NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study. Gut 46 30448772
2014 Decreased expression of NKG2D, NKp46, DNAM-1 receptors, and intracellular perforin and STAT-1 effector molecules in NK cells and their dim and bright subsets in metastatic melanoma patients. Melanoma research 46 24769842
2015 Expression of NKp30, NKp46 and DNAM-1 activating receptors on resting and IL-2 activated NK cells from healthy donors according to CMV-serostatus and age. Biogerontology 44 25991472
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
2015 Lysis of HIV-1-infected autologous CD4+ primary T cells by interferon-alpha-activated NK cells requires NKp46 and NKG2D. AIDS (London, England) 40 26372382
2011 NKp46+ cells express granulysin in multiple cutaneous adverse drug reactions. Allergy 40 21819408
2016 NCR1 Expression Identifies Canine Natural Killer Cell Subsets with Phenotypic Similarity to Human Natural Killer Cells. Frontiers in immunology 39 27933061
2007 Expression of ligands to NKp46 in benign and malignant melanocytes. The Journal of investigative dermatology 39 17972960
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
2013 Expression of the activating receptor, NKp46 (CD335), in human natural killer and T-cell neoplasia. American journal of clinical pathology 36 24225754
2016 Overexpression of CD158 and NKG2A Inhibitory Receptors and Underexpression of NKG2D and NKp46 Activating Receptors on NK Cells in Acute Myeloid Leukemia. Archives of medical research 35 26876298
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
2016 Neutrophils can disarm NK cell response through cleavage of NKp46. Journal of leukocyte biology 34 27587403
2018 NKp46 Calibrates Tumoricidal Potential of Type 1 Innate Lymphocytes by Regulating TRAIL Expression. Journal of immunology (Baltimore, Md. : 1950) 33 29661825
2018 Circulating NKp46+ Natural Killer cells have a potential regulatory property and predict distinct survival in Non-Small Cell Lung Cancer. Oncoimmunology 33 30713781
2011 NKp46 defines ovine cells that have characteristics corresponding to NK cells. Veterinary research 33 21345198
2016 Porcine CD3(+)NKp46(+) Lymphocytes Have NK-Cell Characteristics and Are Present in Increased Frequencies in the Lungs of Influenza-Infected Animals. Frontiers in immunology 32 27471504
2014 NKp46+ CD3+ cells: a novel nonconventional T cell subset in cattle exhibiting both NK cell and T cell features. Journal of immunology (Baltimore, Md. : 1950) 32 24639352
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
2014 Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a. Cellular & molecular immunology 32 25435072
2012 CD158k/KIR3DL2 and NKp46 are frequently expressed in transformed mycosis fungoides. Experimental dermatology 32 22621189
2013 Successfully treated HIV-infected patients have differential expression of NK cell receptors (NKp46 and NKp30) according to AIDS status at presentation. Immunology letters 31 23538009
2013 Anti-HIV antibody-dependent activation of NK cells impairs NKp46 expression. Journal of immunology (Baltimore, Md. : 1950) 31 24319263
2011 Expansion of 2B4+ natural killer (NK) cells and decrease in NKp46+ NK cells in response to influenza. Immunology 31 21214542
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 30 32204481
2014 An NCR1-based chimeric receptor endows T-cells with multiple anti-tumor specificities. Oncotarget 29 25431955
2013 Characterization of a novel NKG2D and NKp46 double-mutant mouse reveals subtle variations in the NK cell repertoire. Blood 29 23649470
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
2024 GPX4 restricts ferroptosis of NKp46+ILC3s to control intestinal inflammation. Cell death & disease 28 39300068
2018 HIF-1α induces immune escape of prostate cancer by regulating NCR1/NKp46 signaling through miR-224. Biochemical and biophysical research communications 28 29885835
2018 Cutting Edge: Check Your Mice-A Point Mutation in the Ncr1 Locus Identified in CD45.1 Congenic Mice with Consequences in Mouse Susceptibility to Infection. Journal of immunology (Baltimore, Md. : 1950) 27 29440507
2018 MiR-544 promotes immune escape through downregulation of NCR1/NKp46 via targeting RUNX3 in liver cancer. Cancer cell international 27 29636640
2011 Lymphotoxin-β receptor-independent development of intestinal IL-22-producing NKp46+ innate lymphoid cells. European journal of immunology 27 21341264

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