{"gene":"HLA-F","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1990,"finding":"HLA-F (HLA-5.4) encodes an intact class I protein with a shortened cytoplasmic tail, five altered residues in the antigen-binding groove (three non-conservative), and a 3' untranslated region containing a novel multigene family. The gene is expressed in B lymphoblastoid cell lines, resting T cells, and skin cells but not in the T cell line Molt 4, indicating a tissue-specific expression pattern distinct from classical class I genes.","method":"Gene sequencing, RNase protection assay, Northern analysis, protein sequence analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — original characterization with multiple orthogonal methods (sequencing, RNase protection, Northern), replicated by independent group (PMID:1707659)","pmids":["1688605"],"is_preprint":false},{"year":1990,"finding":"HLA-F (Dew3) protein expressed after transfection into a human EBV-transformed B cell line is located intracellularly. The transcribed mRNA is shorter than classical class I mRNAs due to an altered acceptor splice site that removes exon 7. Expression is restricted to B cell lines and peripheral blood lymphocytes and is absent from T cell lines, fibroblasts, and myelomonocytic leukaemia.","method":"cDNA cloning, transfection, immunolocalization, tissue expression analysis","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transfection with protein detection, single lab but consistent with PMID:1688605","pmids":["1707659"],"is_preprint":false},{"year":2000,"finding":"HLA-F heavy chain refolded with β2-microglobulin forms a stable complex. HLA-F is predominantly intracellular, contains an immature (endoglycosidase H-sensitive) oligosaccharide indicating ER retention, and thermostability assays indicate it is expressed as an empty heterodimer devoid of peptide. HLA-F associates with calreticulin and TAP, components of the conventional class I assembly pathway, yet IFN-γ treatment induces HLA-F mRNA and protein without producing cell surface expression.","method":"Recombinant protein refolding, immunoprecipitation, endoglycosidase H assay, thermostability assay, Western blot, flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (refolding, endoH, thermostability, co-IP with TAP/calreticulin) in single study, consistent with independent findings (PMID:11169396)","pmids":["10605026"],"is_preprint":false},{"year":2000,"finding":"HLA-F tetramers (HLA-F heavy chain refolded with β2-microglobulin) bind peripheral blood monocytes and B cells. Transfection of the inhibitory receptors ILT2 (LIR1) and ILT4 (LIR2) into non-binding cells confers HLA-F tetramer binding. Surface plasmon resonance demonstrated a direct molecular interaction between HLA-F and ILT2 and ILT4.","method":"Recombinant protein refolding, tetramer staining, transfection, surface plasmon resonance","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding demonstrated by two orthogonal methods (tetramer staining + SPR), functional validation by transfection","pmids":["11169396"],"is_preprint":false},{"year":2000,"finding":"HLA-F gene transcription is inducible by NF-κB through the κB1 site of enhancer A, is responsive to IFN-γ through the ISRE element, and is inducible by CIITA through the SXY regulatory module, distinguishing its transcriptional regulation from HLA-G (which lacks responsiveness to NF-κB, IRF1, and CIITA) and from HLA-E.","method":"Promoter sequence analysis, transactivation assays (reporter gene/functional promoter studies)","journal":"Human immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter transactivation experiments, single lab","pmids":["11137213"],"is_preprint":false},{"year":2003,"finding":"HLA-F surface expression on B lymphoblastoid and monocyte cell lines is independent of TAP function. Of the two glycosylation forms detected on the surface, an endoglycosidase H-sensitive form is tapasin-independent, whereas an endoglycosidase H-resistant form is tapasin-dependent, indicating two distinct pathways to the cell surface.","method":"Flow cytometry, endoglycosidase H assay, analysis of TAP-deficient and tapasin-deficient cell lines","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic cell-line models (TAP/tapasin deficient) plus biochemical glycosylation assays, multiple orthogonal methods","pmids":["14607927"],"is_preprint":false},{"year":2006,"finding":"HLA-F export from the endoplasmic reticulum (ER) depends entirely on its cytoplasmic tail, unlike classical class I molecules. Two export motifs were identified: a C-terminal valine residue that functions in ER export and interacts with COPII coat complex, and an RxR motif that plays an important role in anterograde transport and binds 14-3-3 proteins.","method":"Deletion and point mutagenesis of cytoplasmic tail, cell surface expression assays, binding assays for COPII and 14-3-3 proteins","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis identifying specific export motifs plus biochemical binding to COPII and 14-3-3, two orthogonal methods in single rigorous study","pmids":["16709803"],"is_preprint":false},{"year":2010,"finding":"HLA-F is expressed intracellularly in resting B cells, T cells, NK cells, and monocytes but translocates to the cell surface upon lymphocyte activation. CD4+CD25+ regulatory T cells do not upregulate surface HLA-F upon activation, whereas CD4+CD25- T cells show strong surface HLA-F induction. Individuals genetically deficient for TAP or tapasin show the same activation-induced surface expression profile but with altered kinetics.","method":"Western blot, flow cytometry, activation of primary lymphocytes, analysis of TAP/tapasin-deficient donors","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell types, genetic deficiency models, reciprocal surface/intracellular staining, consistent with prior biochemistry","pmids":["20865824"],"is_preprint":false},{"year":2010,"finding":"HLA-F on the surface of B lymphoblastoid cells and activated lymphocytes is expressed as an open conformer without bound peptide. HLA-F physically interacts with MHC class I heavy chain only when the heavy chain is in the open conformer (peptide-free) form; trimeric (peptide-loaded) MHC-I does not interact. This interaction was demonstrated by co-immunoprecipitation and surface plasmon resonance, and indirectly confirmed by coincident tetramer and MHC-I heavy chain colocalization on cell surfaces.","method":"Co-immunoprecipitation, surface plasmon resonance, peptide-binding profiling, tetramer colocalization, perturbation of MHC-I structure","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted biochemical interaction confirmed by three orthogonal methods (co-IP, SPR, cell-surface colocalization) in single study","pmids":["20483783"],"is_preprint":false},{"year":2013,"finding":"KIR3DL2 and KIR2DS4 physically and functionally interact with HLA-F expressed as a free open conformer devoid of peptide. Classical MHC-I open conformers also serve as ligands, defining HLA-F as a prototypical MHC-I open conformer ligand for KIR receptors.","method":"Surface plasmon resonance, functional NK cell assays, cell binding experiments","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical binding (SPR) plus functional NK cell assays, replicated in subsequent studies","pmids":["24018270"],"is_preprint":false},{"year":2013,"finding":"HLA-F and MHC-I open conformers on activated cells participate in a TAP- and tapasin-independent cross-presentation pathway for exogenous proteins, sensitive to inhibitors of lysosomal enzymes and dependent on MHC-I allotype-specific epitope recognition for antigen uptake.","method":"In vitro antigen cross-presentation assays, inhibition of TAP/tapasin/lysosomal enzymes, activated lymphocyte and monocyte models","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro pathway dissection with pharmacological and genetic inhibitors, single lab","pmids":["23851683"],"is_preprint":false},{"year":2016,"finding":"KIR3DS1 binds HLA-F open conformers (not peptide-loaded HLA-F) with high affinity; this was confirmed biochemically and functionally. Primary KIR3DS1+ NK cells degranulate and produce antiviral cytokines upon encountering HLA-F and inhibit HIV-1 replication in vitro. Activation of CD4+ T cells induces surface HLA-F expression, enabling KIR3DS1 binding; HIV-1 infection further increases HLA-F transcription but decreases KIR3DS1 binding, suggesting immune evasion.","method":"Screening of 100 HLA class I proteins, surface plasmon resonance, primary NK cell degranulation assay, cytokine production assay, HIV-1 replication assay, flow cytometry","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — large-scale binding screen confirmed biochemically and functionally, multiple orthogonal methods, independently replicated (PMID:27649529, PMID:31270222)","pmids":["27455421"],"is_preprint":false},{"year":2016,"finding":"KIR3DS1 but not KIR3DL1 physically binds HLA-F open conformers and other MHC-I open conformers, as measured by surface plasmon resonance. This was confirmed by biochemical pulldown from cell lines and heterodimerization experiments with recombinant proteins. KIR3DS1 ligation by HLA-F triggers granule exocytosis in activated NK cells.","method":"Surface plasmon resonance, biochemical pulldown, recombinant protein heterodimerization, granule exocytosis assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical and functional methods, corroborates and extends PMID:27455421","pmids":["27649529"],"is_preprint":false},{"year":2018,"finding":"KIR3DS1 on primary NK cells is activated by HLA-F expressed on HIV-infected CD4+ T cells. Blocking the HLA-F/KIR3DS1 interaction with KIR3DS1-Fc chimeric protein or anti-HLA-F monoclonal antibody reduces the frequency of activated KIR3DS1+ NK cells, directly demonstrating that the HLA-F/KIR3DS1 interaction is sufficient to trigger NK cell functions including CCL4, IFN-γ, and CD107a expression.","method":"Co-culture of HIV-infected CD4+ T cells with primary NK cells, blocking antibody experiments, intracellular cytokine staining, flow cytometry","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — blocking experiments with two independent reagents (KIR3DS1-Fc and anti-HLA-F mAb) plus exclusive gating, replicated by independent group (PMID:29743316)","pmids":["31270222"],"is_preprint":false},{"year":2018,"finding":"HLA-F expressed on HLA-null 721.221 cells (both untreated and acid-pulsed) activates primary KIR3DS1+ NK cells for CCL4/IFN-γ secretion and CD107a expression. Blocking the HLA-F/KIR3DS1 interaction reduces this activation, confirming that HLA-F ligation is sufficient to activate KIR3DS1+ NK cells.","method":"Transfection of HLA-null cells, co-culture with primary NK cells, blocking antibody and KIR3DS1-Fc experiments, flow cytometry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — HLA-null cell system with blocking experiments, corroborates PMID:31270222 using complementary approach","pmids":["29743316"],"is_preprint":false},{"year":2018,"finding":"KIR3DS1/HLA-F interaction contributes to NK cell-mediated control of HCV replication. HLA-F is upregulated on HCV-infected cells, and interactions between KIR3DS1 and HLA-F activate NK cells to control HCV in cell culture.","method":"In vitro HCV cell culture, humanized mouse liver models, primary liver biopsy analysis, NK cell functional assays","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems but mechanistic detail in the abstract is limited","pmids":["30031767"],"is_preprint":false},{"year":2019,"finding":"HLA-F*01:01 presents peptides of non-canonical length (preferred length of 16 residues) without a defined N-terminal anchor. Stable peptide-HLA-F*01:01 complexes were recovered and peptide characteristics were analyzed; source proteins of HLA-F-restricted peptides are predominantly described as interacting with HIV proteins.","method":"Stable pHLA-F*01:01 complex recovery, mass spectrometry peptide analysis","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct peptide elution and MS analysis from native complexes, single lab","pmids":["30941482"],"is_preprint":false},{"year":2019,"finding":"HLA-F allelic variants (F*01:01, F*01:03, F*01:04) present peptides with 8–24 amino acid length and C-terminal Lys preference, but with no overlap in proteomic source between allelic variants despite being selected from the same cellular content. Recombinant soluble KIR3DS1 does not bind peptide-loaded HLA-F complexes but binds when HLA-F is in the open conformer form (after acid elution of peptides), and hemoglobin peptides dominant in HIV-infected CD4+ T cells reduce KIR3DS1 binding to HLA-F.","method":"Soluble HLA technology, LC-MS peptide analysis, K562 cell recombinant expression, KIR3DS1-Fc binding assay, proteome analysis of CD4+/HIV+ vs CD4+/HIV- cells","journal":"International journal of molecular sciences / International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — soluble HLA + MS + receptor binding experiments, single lab, two related studies","pmids":["31717259","33126487"],"is_preprint":false},{"year":2014,"finding":"HLA-F gene expression is induced by Japanese encephalitis virus (JEV) infection through NF-κB. shRNA-mediated knockdown of the p65 subunit of NF-κB inhibited JEV-induced HLA-F expression in amniotic and human brain microvascular endothelial cell lines. TNF-α treatment also induced HLA-F expression via NF-κB, confirmed by luciferase reporter assays using HLA-F enhancer A elements.","method":"shRNA knockdown, luciferase reporter assay, Western blot, RT-PCR","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown plus reporter assay confirming NF-κB-dependent transcription, single lab","pmids":["25461528"],"is_preprint":false},{"year":2020,"finding":"BK polyomavirus infection significantly increases surface expression of HLA-F on kidney tubular cells in vitro and in kidney biopsy samples from patients with BK polyomavirus-associated nephropathy. Upregulated HLA-F increases KIR3DS1 binding to infected cells and activates primary KIR3DS1+ NK cells.","method":"In vitro BK polyomavirus infection model, flow cytometry, primary NK cell activation assays, kidney biopsy immunostaining","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro infection model plus ex vivo biopsy validation, consistent with established HLA-F/KIR3DS1 mechanism","pmids":["33359499"],"is_preprint":false},{"year":2018,"finding":"A derived A allele at SNP rs2523393 in a distal enhancer of HLA-F creates a GATA2 binding site in a progesterone-responsive enhancer that physically loops to the HLA-F promoter. This results in increased HLA-F expression. HLA-F expression is upregulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells.","method":"eQTL analysis (GTEx replication), luciferase reporter assay, chromatin conformation capture (enhancer-promoter looping), GATA2 binding assay, endometrial cell culture with progesterone treatment","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enhancer activity confirmed by reporter assay and looping experiment, single lab","pmids":["30245028"],"is_preprint":false},{"year":2021,"finding":"Forced expression of HLA-F in glioma cells promoted aerobic glycolysis via increased HK2 (hexokinase 2) protein stabilization; silencing HK2 reduced HLA-F-mediated glycolysis and cell proliferation. Anti-HLA-F antibody treatment suppressed growth of HLA-F-expressing cells in immunodeficient mice.","method":"Lentiviral overexpression, shRNA knockdown, in vitro glycolysis assays, xenograft tumor model, anti-HLA-F antibody treatment","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function and gain-of-function with specific metabolic readout and rescue by HK2 knockdown, single lab","pmids":["33867844"],"is_preprint":false},{"year":2025,"finding":"HLA-F promotes trophoblast proliferation via PKM2-dependent glycolysis. HLA-F overexpression increases PKM2 protein expression and enzymatic activity, enhancing glycolysis. Mechanistically, HLA-F binds the PKM gene promoter (shown by ChIP-seq) to upregulate PKM2 transcription, and also promotes PKM2 activity by downregulating lactylation at residue K305. Silencing PKM2 abrogates HLA-F-mediated glycolysis and proliferation. HLA-F expression is reduced in preeclamptic trophoblasts.","method":"ChIP-seq, 4D label-free quantitative proteomics, overexpression/siRNA knockdown, glycolysis assays, CCK8/MTT/colony formation, Mini-PDX model","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP-seq for direct DNA binding plus proteomic lactylation analysis plus rescue experiments, single lab, multiple orthogonal methods","pmids":["40251569"],"is_preprint":false},{"year":2023,"finding":"HLA-F overexpression in trophoblast (Jar) cells promotes cell proliferation, invasion, and migration, while knockdown inhibits these functions. In NK-92MI cells, HLA-F overexpression increases secretion of immunoregulatory cytokines CSF1 and CCL22 and promotes adaptive NKG2C+ NK cell transformation.","method":"Lentiviral overexpression, siRNA knockdown, proliferation/invasion/migration assays, cytokine measurement, flow cytometry for NK cell phenotype","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with specific cellular readouts, single lab","pmids":["37854606"],"is_preprint":false}],"current_model":"HLA-F is a non-classical MHC class Ib molecule that resides predominantly in the ER as an empty (peptide-free) β2-microglobulin-associated heterodimer associated with TAP and calreticulin, trafficking to the cell surface upon lymphocyte or trophoblast activation via a cytoplasmic tail-dependent mechanism involving COPII and 14-3-3 proteins; at the surface it preferentially exists as an open conformer (free heavy chain) that serves as the primary ligand for the activating NK receptor KIR3DS1 (and also binds inhibitory ILT2/ILT4), thereby activating KIR3DS1+ NK cells to control viral infections including HIV and HCV, while peptide-loaded HLA-F can present non-canonical-length peptides (8–24 aa, C-terminal Lys) that, when derived from hemoglobin in HIV-infected cells, abrogate KIR3DS1 binding, and intracellularly HLA-F also regulates trophoblast proliferation through PKM2-dependent glycolysis by binding the PKM promoter and modulating K305 lactylation of PKM2."},"narrative":{"mechanistic_narrative":"HLA-F is a non-classical MHC class Ib molecule encoded by a class I gene with a shortened cytoplasmic tail and an antigen-binding groove divergent from classical class I, displaying a tissue-restricted expression pattern [PMID:1688605, PMID:1707659]. It is synthesized as a β2-microglobulin-associated heavy chain that is retained predominantly in the ER as an empty, peptide-free heterodimer in association with the conventional class I assembly machinery TAP and calreticulin [PMID:10605026]. Unlike classical class I, ER export of HLA-F is governed entirely by its cytoplasmic tail through a C-terminal valine that engages the COPII coat and an RxR motif that binds 14-3-3 proteins [PMID:16709803], and its surface delivery proceeds through both tapasin-dependent and tapasin-independent routes [PMID:14607927]. HLA-F is intracellular in resting lymphocytes, NK cells, and monocytes but translocates to the surface upon lymphocyte activation, where it is displayed largely as an open conformer (free heavy chain) that physically associates with peptide-free MHC-I heavy chains [PMID:20865824, PMID:20483783]. In this open-conformer state HLA-F is the high-affinity ligand for the activating NK receptor KIR3DS1, and ligation triggers degranulation and antiviral cytokine production by primary NK cells; this axis drives NK-cell control of HIV-1 and HCV, and HLA-F is upregulated on cells infected with HIV, HCV, BK polyomavirus, and Japanese encephalitis virus, the latter via NF-κB [PMID:27455421, PMID:27649529, PMID:31270222, PMID:30031767, PMID:25461528, PMID:33359499]. HLA-F open conformers also bind the inhibitory receptors ILT2 and ILT4 [PMID:11169396]. Although it can present non-canonical-length peptides (8–24 residues with C-terminal lysine preference), peptide loading abolishes KIR3DS1 binding, and HIV-derived hemoglobin peptides dominant in infected cells reduce KIR3DS1 engagement, providing a route to immune evasion [PMID:27455421, PMID:30941482, PMID:31717259, PMID:33126487]. Beyond immune surveillance, HLA-F drives trophoblast proliferation and invasion by promoting glycolysis through PKM2 — binding the PKM promoter to upregulate transcription and reducing K305 lactylation to enhance enzymatic activity — and analogously stabilizes HK2 to fuel aerobic glycolysis and proliferation in glioma cells [PMID:33867844, PMID:40251569, PMID:37854606].","teleology":[{"year":1990,"claim":"Established that HLA-F is a distinct class I gene rather than a classical HLA allele, defined by a shortened cytoplasmic tail, altered groove residues, and restricted tissue expression.","evidence":"Gene/protein sequencing, RNase protection, Northern analysis, and cDNA transfection with immunolocalization in B cell lines","pmids":["1688605","1707659"],"confidence":"High","gaps":["Did not establish function or surface ligand","Intracellular retention mechanism not yet defined"]},{"year":2000,"claim":"Showed HLA-F is an ER-retained, peptide-empty β2m heterodimer engaged with the classical assembly machinery, posing the question of why it does not reach the surface like classical class I.","evidence":"Recombinant refolding, endoglycosidase H sensitivity, thermostability assay, and co-IP with TAP and calreticulin","pmids":["10605026"],"confidence":"High","gaps":["Trigger for surface translocation unknown","Functional consequence of empty heterodimer not defined"]},{"year":2000,"claim":"Identified the first receptors for HLA-F by showing it binds the inhibitory ILT2 and ILT4, establishing HLA-F as a functional ligand.","evidence":"Tetramer staining of monocytes/B cells, receptor transfection, and surface plasmon resonance","pmids":["11169396"],"confidence":"High","gaps":["Conformational state of HLA-F required for binding not yet resolved","Downstream signaling not addressed"]},{"year":2000,"claim":"Defined the transcriptional control of HLA-F as responsive to NF-κB, IFN-γ/ISRE, and CIITA, distinguishing it from HLA-G and HLA-E.","evidence":"Promoter analysis and reporter transactivation assays","pmids":["11137213"],"confidence":"Medium","gaps":["Endogenous physiological inducers not tested","Link between transcription and surface protein not established"]},{"year":2003,"claim":"Resolved that surface HLA-F arrives by two pathways — a TAP-independent, tapasin-independent endoH-sensitive route and a tapasin-dependent endoH-resistant route — separating it from canonical class I trafficking.","evidence":"Flow cytometry and endoH assays in TAP- and tapasin-deficient cell lines","pmids":["14607927"],"confidence":"High","gaps":["Molecular machinery driving export not identified","Functional difference between the two surface forms unclear"]},{"year":2006,"claim":"Identified the cytoplasmic tail motifs controlling HLA-F ER export, explaining how its trafficking is uncoupled from classical class I.","evidence":"Tail mutagenesis with surface expression assays and binding to COPII and 14-3-3 proteins","pmids":["16709803"],"confidence":"High","gaps":["Signal that initiates tail-dependent export upon activation unknown","Regulation of 14-3-3 engagement not defined"]},{"year":2010,"claim":"Demonstrated that HLA-F surfaces upon lymphocyte activation as a peptide-free open conformer that associates specifically with open (peptide-free) MHC-I heavy chains, defining its conformational identity.","evidence":"Activation of primary lymphocytes, reciprocal surface/intracellular staining, co-IP, SPR, and tetramer colocalization","pmids":["20865824","20483783"],"confidence":"High","gaps":["Activating NK receptor for the open conformer not yet identified","Significance of regulatory T cell exclusion from upregulation unclear"]},{"year":2013,"claim":"Established HLA-F as a prototypical MHC-I open-conformer ligand for KIR receptors, showing KIR3DL2 and KIR2DS4 engage peptide-free HLA-F.","evidence":"SPR, cell binding, and functional NK cell assays","pmids":["24018270"],"confidence":"High","gaps":["Did not yet identify the dominant high-affinity activating receptor","In vivo relevance not addressed"]},{"year":2013,"claim":"Described a TAP/tapasin-independent, lysosome-dependent cross-presentation pathway involving HLA-F and MHC-I open conformers on activated cells.","evidence":"In vitro cross-presentation assays with TAP/tapasin/lysosomal inhibition in activated lymphocyte and monocyte models","pmids":["23851683"],"confidence":"Medium","gaps":["Single-lab in vitro pathway dissection","Physiological contribution of this pathway unquantified"]},{"year":2016,"claim":"Identified KIR3DS1 as the high-affinity activating receptor for HLA-F open conformers and linked the interaction to NK-cell control of HIV-1, with HIV reducing KIR3DS1 binding as evasion.","evidence":"Screen of 100 class I proteins, SPR, primary NK degranulation/cytokine assays, HIV-1 replication assays, and biochemical pulldown/granule exocytosis","pmids":["27455421","27649529"],"confidence":"High","gaps":["Structural basis of KIR3DS1/HLA-F recognition not solved","In vivo NK control quantification limited"]},{"year":2018,"claim":"Confirmed that HLA-F engagement is sufficient to activate KIR3DS1+ NK cells using independent blocking reagents and HLA-null cell systems, including against HIV-infected and HCV-infected cells.","evidence":"Co-culture with HIV-infected CD4+ T cells and HLA-null transfectants, KIR3DS1-Fc and anti-HLA-F blocking, intracellular cytokine staining, plus HCV culture and humanized models","pmids":["31270222","29743316","30031767"],"confidence":"High","gaps":["Mechanistic detail for HCV control limited","Quantitative contribution in vivo not fully resolved"]},{"year":2019,"claim":"Characterized the HLA-F peptide repertoire (non-canonical 8–24 aa, C-terminal Lys, allele-specific sources) and showed peptide loading abolishes KIR3DS1 binding, with HIV-derived hemoglobin peptides reducing engagement.","evidence":"Soluble HLA complex recovery, LC-MS peptide elution, recombinant expression, KIR3DS1-Fc binding, and HIV+ vs HIV- proteome comparison","pmids":["30941482","31717259","33126487"],"confidence":"Medium","gaps":["Single lab for peptide elution studies","Physiological role of peptide-loaded HLA-F unclear"]},{"year":2018,"claim":"Extended HLA-F induction to multiple infection and physiological contexts, identifying NF-κB-driven induction by JEV/TNF-α and a progesterone-responsive enhancer creating a GATA2 site that loops to the promoter to elevate endometrial expression.","evidence":"shRNA knockdown of p65, luciferase reporters, eQTL analysis, and chromatin conformation capture in endometrial cells","pmids":["25461528","30245028"],"confidence":"Medium","gaps":["Single-lab regulatory studies","Connection between transcriptional induction and functional surface display not always demonstrated"]},{"year":2020,"claim":"Showed BK polyomavirus upregulates surface HLA-F in kidney tubular cells and nephropathy biopsies, increasing KIR3DS1 binding and NK activation, broadening the antiviral surveillance role.","evidence":"In vitro infection model, flow cytometry, primary NK activation assays, and kidney biopsy immunostaining","pmids":["33359499"],"confidence":"Medium","gaps":["Causal role in nephropathy outcome not established","Single-lab validation"]},{"year":2025,"claim":"Revealed a cell-intrinsic, non-immune function in which HLA-F drives proliferation through glycolysis — in trophoblasts via PKM promoter binding and PKM2 K305 delactylation, and analogously via HK2 stabilization in glioma.","evidence":"ChIP-seq, 4D label-free proteomics, overexpression/knockdown with PKM2 or HK2 rescue, glycolysis and proliferation assays, and xenograft/Mini-PDX models","pmids":["40251569","33867844","37854606"],"confidence":"Medium","gaps":["Mechanism by which an MHC molecule accesses chromatin to bind the PKM promoter not explained","Single-lab studies for each system","Relationship between surface-ligand and intracellular metabolic functions undefined"]},{"year":null,"claim":"How HLA-F reconciles its dual identities — surface open-conformer ligand for KIR3DS1/ILT receptors versus an intracellular regulator of glycolytic gene expression — and the structural basis of KIR3DS1 recognition remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal/cryo-EM structure of HLA-F/KIR3DS1 in the timeline","Mechanism linking nuclear/chromatin function to a class I cell-surface molecule unexplained","Whether peptide-loaded and open-conformer pools are interconverted in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,9,11,12,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[22]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[22]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,5,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,8,11,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,9,11,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[21,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,15,19]}],"complexes":[],"partners":["B2M","KIR3DS1","TAP","CALR","LILRB1","LILRB2","YWHA?","KIR3DL2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P30511","full_name":"HLA class I histocompatibility antigen, alpha chain F","aliases":["CDA12","HLA F antigen","Leukocyte antigen F","MHC class I antigen F"],"length_aa":346,"mass_kda":39.1,"function":"Non-classical major histocompatibility class Ib molecule postulated to play a role in immune surveillance, immune tolerance and inflammation. Functions in two forms, as a heterotrimeric complex with B2M/beta-2 microglobulin and a peptide (peptide-bound HLA-F-B2M) and as an open conformer (OC) devoid of peptide and B2M (peptide-free OC). In complex with B2M, presents non-canonical self-peptides carrying post-translational modifications, particularly phosphorylated self-peptides. Peptide-bound HLA-F-B2M acts as a ligand for LILRB1 inhibitory receptor, a major player in maternal-fetal tolerance. Peptide-free OC acts as a ligand for KIR3DS1 and KIR3DL2 receptors (PubMed:28636952). Upon interaction with activating KIR3DS1 receptor on NK cells, triggers NK cell degranulation and anti-viral cytokine production (PubMed:27455421). Through interaction with KIR3DL2 receptor, inhibits NK and T cell effector functions (PubMed:24018270). May interact with other MHC class I OCs to cross-present exogenous viral, tumor or minor histompatibility antigens to cytotoxic CD8+ T cells, triggering effector and memory responses (PubMed:23851683). May play a role in inflammatory responses in the peripheral nervous system. Through interaction with KIR3DL2, may protect motor neurons from astrocyte-induced toxicity (PubMed:26928464)","subcellular_location":"Cell membrane; Early endosome membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/P30511/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HLA-F","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HLA-F","total_profiled":1310},"omim":[{"mim_id":"620778","title":"KILLER CELL IMMUNOGLOBULIN-LIKE RECEPTOR, THREE DOMAINS, SHORT CYTOPLASMIC TAIL, 1; KIR3DS1","url":"https://www.omim.org/entry/620778"},{"mim_id":"615797","title":"HLA COMPLEX GROUP 9, NONCODING; HCG9","url":"https://www.omim.org/entry/615797"},{"mim_id":"615714","title":"POLR1H ANTISENSE, PSEUDOGENE; POLR1HASP","url":"https://www.omim.org/entry/615714"},{"mim_id":"613609","title":"HOMEOSTATIC IRON REGULATOR; HFE","url":"https://www.omim.org/entry/613609"},{"mim_id":"607525","title":"POLYMERASE I, RNA, SUBUNIT H; POLR1H","url":"https://www.omim.org/entry/607525"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":172.8}],"url":"https://www.proteinatlas.org/search/HLA-F"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P30511","domains":[{"cath_id":"3.30.500.10","chopping":"23-200","consensus_level":"high","plddt":97.0535,"start":23,"end":200},{"cath_id":"2.60.40.10","chopping":"206-293","consensus_level":"high","plddt":96.4612,"start":206,"end":293}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P30511","model_url":"https://alphafold.ebi.ac.uk/files/AF-P30511-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P30511-F1-predicted_aligned_error_v6.png","plddt_mean":89.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HLA-F","jax_strain_url":"https://www.jax.org/strain/search?query=HLA-F"},"sequence":{"accession":"P30511","fasta_url":"https://rest.uniprot.org/uniprotkb/P30511.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P30511/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P30511"}},"corpus_meta":[{"pmid":"2249951","id":"PMC_2249951","title":"Differential expression of HLA-E, HLA-F, and HLA-G transcripts in human tissue.","date":"1990","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2249951","citation_count":225,"is_preprint":false},{"pmid":"1688605","id":"PMC_1688605","title":"Human leukocyte antigen F (HLA-F). 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Polyposis Syndrome.","date":"2022","source":"The Journal of molecular diagnostics : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/35447336","citation_count":3,"is_preprint":false},{"pmid":"38390869","id":"PMC_38390869","title":"Diversity in the HLA-I Recognition of HLA-F Monoclonal Antibodies: HLA-F or HLA-Ib Monospecific, HLA-E or HLA-G Bispecific Antibodies with or without HLA-Ia Reactivity.","date":"2024","source":"Antibodies (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38390869","citation_count":3,"is_preprint":false},{"pmid":"33420581","id":"PMC_33420581","title":"DNA Methylation and Transcription of HLA-F and Serum Cytokines Relate to Chinese Medicine Syndrome Classification in Patients with Chronic Hepatitis B.","date":"2021","source":"Chinese journal of integrative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33420581","citation_count":2,"is_preprint":false},{"pmid":"33781967","id":"PMC_33781967","title":"Human leukocyte antigen (HLA)-F and -G gene polymorphisms and haplotypes are associated with malaria susceptibility in the Beninese Toffin children.","date":"2021","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33781967","citation_count":2,"is_preprint":false},{"pmid":"41537416","id":"PMC_41537416","title":"HLA-F: A Non-Classical Gene With Growing Interest.","date":"2026","source":"HLA","url":"https://pubmed.ncbi.nlm.nih.gov/41537416","citation_count":1,"is_preprint":false},{"pmid":"38073430","id":"PMC_38073430","title":"The novel HLA-F*01:16 and HLA-F*01:17 alleles identified in hematopoietic cell donors.","date":"2023","source":"HLA","url":"https://pubmed.ncbi.nlm.nih.gov/38073430","citation_count":1,"is_preprint":false},{"pmid":"39405828","id":"PMC_39405828","title":"Effect modification between HLA-F and CD56 markers reveals differences in survival for triple-negative breast cancer patients.","date":"2024","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39405828","citation_count":1,"is_preprint":false},{"pmid":"40184242","id":"PMC_40184242","title":"Association of HLA-Ib (HLA-G, HLA-E and HLA-F) with spontaneous HBV clearance.","date":"2025","source":"Infectious diseases (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40184242","citation_count":1,"is_preprint":false},{"pmid":"41321564","id":"PMC_41321564","title":"Emerging roles of natural killer cell ligands-HLA-E, HLA-F, HLA-G, MICA, and MICB-in in vitro fertilization outcomes.","date":"2025","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41321564","citation_count":1,"is_preprint":false},{"pmid":"40603242","id":"PMC_40603242","title":"Investigations of HLA-F and HLA-G 3'UTR Polymorphisms in Preeclampsia and Fetal Growth Restriction Indicate a Possible Role of HLA-F-HLA-G Haplotypes and Diplotypes.","date":"2025","source":"HLA","url":"https://pubmed.ncbi.nlm.nih.gov/40603242","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.28.615513","title":"Exploring the Correlation Between UVB Sensitivity and SLE Activity: Insights into UVB-Driven Pathogenesis in Lupus Erythematosus","date":"2024-09-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.28.615513","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46353,"output_tokens":6251,"usd":0.116412,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15031,"output_tokens":4934,"usd":0.099252,"stage2_stop_reason":"end_turn"},"total_usd":0.215664,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"HLA-F (HLA-5.4) encodes an intact class I protein with a shortened cytoplasmic tail, five altered residues in the antigen-binding groove (three non-conservative), and a 3' untranslated region containing a novel multigene family. The gene is expressed in B lymphoblastoid cell lines, resting T cells, and skin cells but not in the T cell line Molt 4, indicating a tissue-specific expression pattern distinct from classical class I genes.\",\n      \"method\": \"Gene sequencing, RNase protection assay, Northern analysis, protein sequence analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — original characterization with multiple orthogonal methods (sequencing, RNase protection, Northern), replicated by independent group (PMID:1707659)\",\n      \"pmids\": [\"1688605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"HLA-F (Dew3) protein expressed after transfection into a human EBV-transformed B cell line is located intracellularly. The transcribed mRNA is shorter than classical class I mRNAs due to an altered acceptor splice site that removes exon 7. Expression is restricted to B cell lines and peripheral blood lymphocytes and is absent from T cell lines, fibroblasts, and myelomonocytic leukaemia.\",\n      \"method\": \"cDNA cloning, transfection, immunolocalization, tissue expression analysis\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transfection with protein detection, single lab but consistent with PMID:1688605\",\n      \"pmids\": [\"1707659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HLA-F heavy chain refolded with β2-microglobulin forms a stable complex. HLA-F is predominantly intracellular, contains an immature (endoglycosidase H-sensitive) oligosaccharide indicating ER retention, and thermostability assays indicate it is expressed as an empty heterodimer devoid of peptide. HLA-F associates with calreticulin and TAP, components of the conventional class I assembly pathway, yet IFN-γ treatment induces HLA-F mRNA and protein without producing cell surface expression.\",\n      \"method\": \"Recombinant protein refolding, immunoprecipitation, endoglycosidase H assay, thermostability assay, Western blot, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (refolding, endoH, thermostability, co-IP with TAP/calreticulin) in single study, consistent with independent findings (PMID:11169396)\",\n      \"pmids\": [\"10605026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HLA-F tetramers (HLA-F heavy chain refolded with β2-microglobulin) bind peripheral blood monocytes and B cells. Transfection of the inhibitory receptors ILT2 (LIR1) and ILT4 (LIR2) into non-binding cells confers HLA-F tetramer binding. Surface plasmon resonance demonstrated a direct molecular interaction between HLA-F and ILT2 and ILT4.\",\n      \"method\": \"Recombinant protein refolding, tetramer staining, transfection, surface plasmon resonance\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding demonstrated by two orthogonal methods (tetramer staining + SPR), functional validation by transfection\",\n      \"pmids\": [\"11169396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HLA-F gene transcription is inducible by NF-κB through the κB1 site of enhancer A, is responsive to IFN-γ through the ISRE element, and is inducible by CIITA through the SXY regulatory module, distinguishing its transcriptional regulation from HLA-G (which lacks responsiveness to NF-κB, IRF1, and CIITA) and from HLA-E.\",\n      \"method\": \"Promoter sequence analysis, transactivation assays (reporter gene/functional promoter studies)\",\n      \"journal\": \"Human immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter transactivation experiments, single lab\",\n      \"pmids\": [\"11137213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HLA-F surface expression on B lymphoblastoid and monocyte cell lines is independent of TAP function. Of the two glycosylation forms detected on the surface, an endoglycosidase H-sensitive form is tapasin-independent, whereas an endoglycosidase H-resistant form is tapasin-dependent, indicating two distinct pathways to the cell surface.\",\n      \"method\": \"Flow cytometry, endoglycosidase H assay, analysis of TAP-deficient and tapasin-deficient cell lines\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic cell-line models (TAP/tapasin deficient) plus biochemical glycosylation assays, multiple orthogonal methods\",\n      \"pmids\": [\"14607927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HLA-F export from the endoplasmic reticulum (ER) depends entirely on its cytoplasmic tail, unlike classical class I molecules. Two export motifs were identified: a C-terminal valine residue that functions in ER export and interacts with COPII coat complex, and an RxR motif that plays an important role in anterograde transport and binds 14-3-3 proteins.\",\n      \"method\": \"Deletion and point mutagenesis of cytoplasmic tail, cell surface expression assays, binding assays for COPII and 14-3-3 proteins\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis identifying specific export motifs plus biochemical binding to COPII and 14-3-3, two orthogonal methods in single rigorous study\",\n      \"pmids\": [\"16709803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HLA-F is expressed intracellularly in resting B cells, T cells, NK cells, and monocytes but translocates to the cell surface upon lymphocyte activation. CD4+CD25+ regulatory T cells do not upregulate surface HLA-F upon activation, whereas CD4+CD25- T cells show strong surface HLA-F induction. Individuals genetically deficient for TAP or tapasin show the same activation-induced surface expression profile but with altered kinetics.\",\n      \"method\": \"Western blot, flow cytometry, activation of primary lymphocytes, analysis of TAP/tapasin-deficient donors\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell types, genetic deficiency models, reciprocal surface/intracellular staining, consistent with prior biochemistry\",\n      \"pmids\": [\"20865824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HLA-F on the surface of B lymphoblastoid cells and activated lymphocytes is expressed as an open conformer without bound peptide. HLA-F physically interacts with MHC class I heavy chain only when the heavy chain is in the open conformer (peptide-free) form; trimeric (peptide-loaded) MHC-I does not interact. This interaction was demonstrated by co-immunoprecipitation and surface plasmon resonance, and indirectly confirmed by coincident tetramer and MHC-I heavy chain colocalization on cell surfaces.\",\n      \"method\": \"Co-immunoprecipitation, surface plasmon resonance, peptide-binding profiling, tetramer colocalization, perturbation of MHC-I structure\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted biochemical interaction confirmed by three orthogonal methods (co-IP, SPR, cell-surface colocalization) in single study\",\n      \"pmids\": [\"20483783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIR3DL2 and KIR2DS4 physically and functionally interact with HLA-F expressed as a free open conformer devoid of peptide. Classical MHC-I open conformers also serve as ligands, defining HLA-F as a prototypical MHC-I open conformer ligand for KIR receptors.\",\n      \"method\": \"Surface plasmon resonance, functional NK cell assays, cell binding experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical binding (SPR) plus functional NK cell assays, replicated in subsequent studies\",\n      \"pmids\": [\"24018270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HLA-F and MHC-I open conformers on activated cells participate in a TAP- and tapasin-independent cross-presentation pathway for exogenous proteins, sensitive to inhibitors of lysosomal enzymes and dependent on MHC-I allotype-specific epitope recognition for antigen uptake.\",\n      \"method\": \"In vitro antigen cross-presentation assays, inhibition of TAP/tapasin/lysosomal enzymes, activated lymphocyte and monocyte models\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro pathway dissection with pharmacological and genetic inhibitors, single lab\",\n      \"pmids\": [\"23851683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR3DS1 binds HLA-F open conformers (not peptide-loaded HLA-F) with high affinity; this was confirmed biochemically and functionally. Primary KIR3DS1+ NK cells degranulate and produce antiviral cytokines upon encountering HLA-F and inhibit HIV-1 replication in vitro. Activation of CD4+ T cells induces surface HLA-F expression, enabling KIR3DS1 binding; HIV-1 infection further increases HLA-F transcription but decreases KIR3DS1 binding, suggesting immune evasion.\",\n      \"method\": \"Screening of 100 HLA class I proteins, surface plasmon resonance, primary NK cell degranulation assay, cytokine production assay, HIV-1 replication assay, flow cytometry\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — large-scale binding screen confirmed biochemically and functionally, multiple orthogonal methods, independently replicated (PMID:27649529, PMID:31270222)\",\n      \"pmids\": [\"27455421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIR3DS1 but not KIR3DL1 physically binds HLA-F open conformers and other MHC-I open conformers, as measured by surface plasmon resonance. This was confirmed by biochemical pulldown from cell lines and heterodimerization experiments with recombinant proteins. KIR3DS1 ligation by HLA-F triggers granule exocytosis in activated NK cells.\",\n      \"method\": \"Surface plasmon resonance, biochemical pulldown, recombinant protein heterodimerization, granule exocytosis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical and functional methods, corroborates and extends PMID:27455421\",\n      \"pmids\": [\"27649529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIR3DS1 on primary NK cells is activated by HLA-F expressed on HIV-infected CD4+ T cells. Blocking the HLA-F/KIR3DS1 interaction with KIR3DS1-Fc chimeric protein or anti-HLA-F monoclonal antibody reduces the frequency of activated KIR3DS1+ NK cells, directly demonstrating that the HLA-F/KIR3DS1 interaction is sufficient to trigger NK cell functions including CCL4, IFN-γ, and CD107a expression.\",\n      \"method\": \"Co-culture of HIV-infected CD4+ T cells with primary NK cells, blocking antibody experiments, intracellular cytokine staining, flow cytometry\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — blocking experiments with two independent reagents (KIR3DS1-Fc and anti-HLA-F mAb) plus exclusive gating, replicated by independent group (PMID:29743316)\",\n      \"pmids\": [\"31270222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HLA-F expressed on HLA-null 721.221 cells (both untreated and acid-pulsed) activates primary KIR3DS1+ NK cells for CCL4/IFN-γ secretion and CD107a expression. Blocking the HLA-F/KIR3DS1 interaction reduces this activation, confirming that HLA-F ligation is sufficient to activate KIR3DS1+ NK cells.\",\n      \"method\": \"Transfection of HLA-null cells, co-culture with primary NK cells, blocking antibody and KIR3DS1-Fc experiments, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — HLA-null cell system with blocking experiments, corroborates PMID:31270222 using complementary approach\",\n      \"pmids\": [\"29743316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KIR3DS1/HLA-F interaction contributes to NK cell-mediated control of HCV replication. HLA-F is upregulated on HCV-infected cells, and interactions between KIR3DS1 and HLA-F activate NK cells to control HCV in cell culture.\",\n      \"method\": \"In vitro HCV cell culture, humanized mouse liver models, primary liver biopsy analysis, NK cell functional assays\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems but mechanistic detail in the abstract is limited\",\n      \"pmids\": [\"30031767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HLA-F*01:01 presents peptides of non-canonical length (preferred length of 16 residues) without a defined N-terminal anchor. Stable peptide-HLA-F*01:01 complexes were recovered and peptide characteristics were analyzed; source proteins of HLA-F-restricted peptides are predominantly described as interacting with HIV proteins.\",\n      \"method\": \"Stable pHLA-F*01:01 complex recovery, mass spectrometry peptide analysis\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct peptide elution and MS analysis from native complexes, single lab\",\n      \"pmids\": [\"30941482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HLA-F allelic variants (F*01:01, F*01:03, F*01:04) present peptides with 8–24 amino acid length and C-terminal Lys preference, but with no overlap in proteomic source between allelic variants despite being selected from the same cellular content. Recombinant soluble KIR3DS1 does not bind peptide-loaded HLA-F complexes but binds when HLA-F is in the open conformer form (after acid elution of peptides), and hemoglobin peptides dominant in HIV-infected CD4+ T cells reduce KIR3DS1 binding to HLA-F.\",\n      \"method\": \"Soluble HLA technology, LC-MS peptide analysis, K562 cell recombinant expression, KIR3DS1-Fc binding assay, proteome analysis of CD4+/HIV+ vs CD4+/HIV- cells\",\n      \"journal\": \"International journal of molecular sciences / International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — soluble HLA + MS + receptor binding experiments, single lab, two related studies\",\n      \"pmids\": [\"31717259\", \"33126487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HLA-F gene expression is induced by Japanese encephalitis virus (JEV) infection through NF-κB. shRNA-mediated knockdown of the p65 subunit of NF-κB inhibited JEV-induced HLA-F expression in amniotic and human brain microvascular endothelial cell lines. TNF-α treatment also induced HLA-F expression via NF-κB, confirmed by luciferase reporter assays using HLA-F enhancer A elements.\",\n      \"method\": \"shRNA knockdown, luciferase reporter assay, Western blot, RT-PCR\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown plus reporter assay confirming NF-κB-dependent transcription, single lab\",\n      \"pmids\": [\"25461528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BK polyomavirus infection significantly increases surface expression of HLA-F on kidney tubular cells in vitro and in kidney biopsy samples from patients with BK polyomavirus-associated nephropathy. Upregulated HLA-F increases KIR3DS1 binding to infected cells and activates primary KIR3DS1+ NK cells.\",\n      \"method\": \"In vitro BK polyomavirus infection model, flow cytometry, primary NK cell activation assays, kidney biopsy immunostaining\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro infection model plus ex vivo biopsy validation, consistent with established HLA-F/KIR3DS1 mechanism\",\n      \"pmids\": [\"33359499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A derived A allele at SNP rs2523393 in a distal enhancer of HLA-F creates a GATA2 binding site in a progesterone-responsive enhancer that physically loops to the HLA-F promoter. This results in increased HLA-F expression. HLA-F expression is upregulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells.\",\n      \"method\": \"eQTL analysis (GTEx replication), luciferase reporter assay, chromatin conformation capture (enhancer-promoter looping), GATA2 binding assay, endometrial cell culture with progesterone treatment\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enhancer activity confirmed by reporter assay and looping experiment, single lab\",\n      \"pmids\": [\"30245028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Forced expression of HLA-F in glioma cells promoted aerobic glycolysis via increased HK2 (hexokinase 2) protein stabilization; silencing HK2 reduced HLA-F-mediated glycolysis and cell proliferation. Anti-HLA-F antibody treatment suppressed growth of HLA-F-expressing cells in immunodeficient mice.\",\n      \"method\": \"Lentiviral overexpression, shRNA knockdown, in vitro glycolysis assays, xenograft tumor model, anti-HLA-F antibody treatment\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function and gain-of-function with specific metabolic readout and rescue by HK2 knockdown, single lab\",\n      \"pmids\": [\"33867844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HLA-F promotes trophoblast proliferation via PKM2-dependent glycolysis. HLA-F overexpression increases PKM2 protein expression and enzymatic activity, enhancing glycolysis. Mechanistically, HLA-F binds the PKM gene promoter (shown by ChIP-seq) to upregulate PKM2 transcription, and also promotes PKM2 activity by downregulating lactylation at residue K305. Silencing PKM2 abrogates HLA-F-mediated glycolysis and proliferation. HLA-F expression is reduced in preeclamptic trophoblasts.\",\n      \"method\": \"ChIP-seq, 4D label-free quantitative proteomics, overexpression/siRNA knockdown, glycolysis assays, CCK8/MTT/colony formation, Mini-PDX model\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP-seq for direct DNA binding plus proteomic lactylation analysis plus rescue experiments, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40251569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HLA-F overexpression in trophoblast (Jar) cells promotes cell proliferation, invasion, and migration, while knockdown inhibits these functions. In NK-92MI cells, HLA-F overexpression increases secretion of immunoregulatory cytokines CSF1 and CCL22 and promotes adaptive NKG2C+ NK cell transformation.\",\n      \"method\": \"Lentiviral overexpression, siRNA knockdown, proliferation/invasion/migration assays, cytokine measurement, flow cytometry for NK cell phenotype\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with specific cellular readouts, single lab\",\n      \"pmids\": [\"37854606\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HLA-F is a non-classical MHC class Ib molecule that resides predominantly in the ER as an empty (peptide-free) β2-microglobulin-associated heterodimer associated with TAP and calreticulin, trafficking to the cell surface upon lymphocyte or trophoblast activation via a cytoplasmic tail-dependent mechanism involving COPII and 14-3-3 proteins; at the surface it preferentially exists as an open conformer (free heavy chain) that serves as the primary ligand for the activating NK receptor KIR3DS1 (and also binds inhibitory ILT2/ILT4), thereby activating KIR3DS1+ NK cells to control viral infections including HIV and HCV, while peptide-loaded HLA-F can present non-canonical-length peptides (8–24 aa, C-terminal Lys) that, when derived from hemoglobin in HIV-infected cells, abrogate KIR3DS1 binding, and intracellularly HLA-F also regulates trophoblast proliferation through PKM2-dependent glycolysis by binding the PKM promoter and modulating K305 lactylation of PKM2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HLA-F is a non-classical MHC class Ib molecule encoded by a class I gene with a shortened cytoplasmic tail and an antigen-binding groove divergent from classical class I, displaying a tissue-restricted expression pattern [#0, #1]. It is synthesized as a β2-microglobulin-associated heavy chain that is retained predominantly in the ER as an empty, peptide-free heterodimer in association with the conventional class I assembly machinery TAP and calreticulin [#2]. Unlike classical class I, ER export of HLA-F is governed entirely by its cytoplasmic tail through a C-terminal valine that engages the COPII coat and an RxR motif that binds 14-3-3 proteins [#6], and its surface delivery proceeds through both tapasin-dependent and tapasin-independent routes [#5]. HLA-F is intracellular in resting lymphocytes, NK cells, and monocytes but translocates to the surface upon lymphocyte activation, where it is displayed largely as an open conformer (free heavy chain) that physically associates with peptide-free MHC-I heavy chains [#7, #8]. In this open-conformer state HLA-F is the high-affinity ligand for the activating NK receptor KIR3DS1, and ligation triggers degranulation and antiviral cytokine production by primary NK cells; this axis drives NK-cell control of HIV-1 and HCV, and HLA-F is upregulated on cells infected with HIV, HCV, BK polyomavirus, and Japanese encephalitis virus, the latter via NF-κB [#11, #12, #13, #15, #18, #19]. HLA-F open conformers also bind the inhibitory receptors ILT2 and ILT4 [#3]. Although it can present non-canonical-length peptides (8–24 residues with C-terminal lysine preference), peptide loading abolishes KIR3DS1 binding, and HIV-derived hemoglobin peptides dominant in infected cells reduce KIR3DS1 engagement, providing a route to immune evasion [#11, #16, #17]. Beyond immune surveillance, HLA-F drives trophoblast proliferation and invasion by promoting glycolysis through PKM2 — binding the PKM promoter to upregulate transcription and reducing K305 lactylation to enhance enzymatic activity — and analogously stabilizes HK2 to fuel aerobic glycolysis and proliferation in glioma cells [#21, #22, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that HLA-F is a distinct class I gene rather than a classical HLA allele, defined by a shortened cytoplasmic tail, altered groove residues, and restricted tissue expression.\",\n      \"evidence\": \"Gene/protein sequencing, RNase protection, Northern analysis, and cDNA transfection with immunolocalization in B cell lines\",\n      \"pmids\": [\"1688605\", \"1707659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish function or surface ligand\", \"Intracellular retention mechanism not yet defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed HLA-F is an ER-retained, peptide-empty β2m heterodimer engaged with the classical assembly machinery, posing the question of why it does not reach the surface like classical class I.\",\n      \"evidence\": \"Recombinant refolding, endoglycosidase H sensitivity, thermostability assay, and co-IP with TAP and calreticulin\",\n      \"pmids\": [\"10605026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger for surface translocation unknown\", \"Functional consequence of empty heterodimer not defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified the first receptors for HLA-F by showing it binds the inhibitory ILT2 and ILT4, establishing HLA-F as a functional ligand.\",\n      \"evidence\": \"Tetramer staining of monocytes/B cells, receptor transfection, and surface plasmon resonance\",\n      \"pmids\": [\"11169396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational state of HLA-F required for binding not yet resolved\", \"Downstream signaling not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the transcriptional control of HLA-F as responsive to NF-κB, IFN-γ/ISRE, and CIITA, distinguishing it from HLA-G and HLA-E.\",\n      \"evidence\": \"Promoter analysis and reporter transactivation assays\",\n      \"pmids\": [\"11137213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous physiological inducers not tested\", \"Link between transcription and surface protein not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved that surface HLA-F arrives by two pathways — a TAP-independent, tapasin-independent endoH-sensitive route and a tapasin-dependent endoH-resistant route — separating it from canonical class I trafficking.\",\n      \"evidence\": \"Flow cytometry and endoH assays in TAP- and tapasin-deficient cell lines\",\n      \"pmids\": [\"14607927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery driving export not identified\", \"Functional difference between the two surface forms unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the cytoplasmic tail motifs controlling HLA-F ER export, explaining how its trafficking is uncoupled from classical class I.\",\n      \"evidence\": \"Tail mutagenesis with surface expression assays and binding to COPII and 14-3-3 proteins\",\n      \"pmids\": [\"16709803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that initiates tail-dependent export upon activation unknown\", \"Regulation of 14-3-3 engagement not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that HLA-F surfaces upon lymphocyte activation as a peptide-free open conformer that associates specifically with open (peptide-free) MHC-I heavy chains, defining its conformational identity.\",\n      \"evidence\": \"Activation of primary lymphocytes, reciprocal surface/intracellular staining, co-IP, SPR, and tetramer colocalization\",\n      \"pmids\": [\"20865824\", \"20483783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activating NK receptor for the open conformer not yet identified\", \"Significance of regulatory T cell exclusion from upregulation unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established HLA-F as a prototypical MHC-I open-conformer ligand for KIR receptors, showing KIR3DL2 and KIR2DS4 engage peptide-free HLA-F.\",\n      \"evidence\": \"SPR, cell binding, and functional NK cell assays\",\n      \"pmids\": [\"24018270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet identify the dominant high-affinity activating receptor\", \"In vivo relevance not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Described a TAP/tapasin-independent, lysosome-dependent cross-presentation pathway involving HLA-F and MHC-I open conformers on activated cells.\",\n      \"evidence\": \"In vitro cross-presentation assays with TAP/tapasin/lysosomal inhibition in activated lymphocyte and monocyte models\",\n      \"pmids\": [\"23851683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab in vitro pathway dissection\", \"Physiological contribution of this pathway unquantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified KIR3DS1 as the high-affinity activating receptor for HLA-F open conformers and linked the interaction to NK-cell control of HIV-1, with HIV reducing KIR3DS1 binding as evasion.\",\n      \"evidence\": \"Screen of 100 class I proteins, SPR, primary NK degranulation/cytokine assays, HIV-1 replication assays, and biochemical pulldown/granule exocytosis\",\n      \"pmids\": [\"27455421\", \"27649529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of KIR3DS1/HLA-F recognition not solved\", \"In vivo NK control quantification limited\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Confirmed that HLA-F engagement is sufficient to activate KIR3DS1+ NK cells using independent blocking reagents and HLA-null cell systems, including against HIV-infected and HCV-infected cells.\",\n      \"evidence\": \"Co-culture with HIV-infected CD4+ T cells and HLA-null transfectants, KIR3DS1-Fc and anti-HLA-F blocking, intracellular cytokine staining, plus HCV culture and humanized models\",\n      \"pmids\": [\"31270222\", \"29743316\", \"30031767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic detail for HCV control limited\", \"Quantitative contribution in vivo not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Characterized the HLA-F peptide repertoire (non-canonical 8–24 aa, C-terminal Lys, allele-specific sources) and showed peptide loading abolishes KIR3DS1 binding, with HIV-derived hemoglobin peptides reducing engagement.\",\n      \"evidence\": \"Soluble HLA complex recovery, LC-MS peptide elution, recombinant expression, KIR3DS1-Fc binding, and HIV+ vs HIV- proteome comparison\",\n      \"pmids\": [\"30941482\", \"31717259\", \"33126487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab for peptide elution studies\", \"Physiological role of peptide-loaded HLA-F unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended HLA-F induction to multiple infection and physiological contexts, identifying NF-κB-driven induction by JEV/TNF-α and a progesterone-responsive enhancer creating a GATA2 site that loops to the promoter to elevate endometrial expression.\",\n      \"evidence\": \"shRNA knockdown of p65, luciferase reporters, eQTL analysis, and chromatin conformation capture in endometrial cells\",\n      \"pmids\": [\"25461528\", \"30245028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab regulatory studies\", \"Connection between transcriptional induction and functional surface display not always demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed BK polyomavirus upregulates surface HLA-F in kidney tubular cells and nephropathy biopsies, increasing KIR3DS1 binding and NK activation, broadening the antiviral surveillance role.\",\n      \"evidence\": \"In vitro infection model, flow cytometry, primary NK activation assays, and kidney biopsy immunostaining\",\n      \"pmids\": [\"33359499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role in nephropathy outcome not established\", \"Single-lab validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a cell-intrinsic, non-immune function in which HLA-F drives proliferation through glycolysis — in trophoblasts via PKM promoter binding and PKM2 K305 delactylation, and analogously via HK2 stabilization in glioma.\",\n      \"evidence\": \"ChIP-seq, 4D label-free proteomics, overexpression/knockdown with PKM2 or HK2 rescue, glycolysis and proliferation assays, and xenograft/Mini-PDX models\",\n      \"pmids\": [\"40251569\", \"33867844\", \"37854606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which an MHC molecule accesses chromatin to bind the PKM promoter not explained\", \"Single-lab studies for each system\", \"Relationship between surface-ligand and intracellular metabolic functions undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HLA-F reconciles its dual identities — surface open-conformer ligand for KIR3DS1/ILT receptors versus an intracellular regulator of glycolytic gene expression — and the structural basis of KIR3DS1 recognition remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal/cryo-EM structure of HLA-F/KIR3DS1 in the timeline\", \"Mechanism linking nuclear/chromatin function to a class I cell-surface molecule unexplained\", \"Whether peptide-loaded and open-conformer pools are interconverted in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 9, 11, 12, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 5, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 8, 11, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 9, 11, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [21, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 15, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"B2M\", \"KIR3DS1\", \"TAP\", \"CALR\", \"LILRB1\", \"LILRB2\", \"YWHA?\", \"KIR3DL2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}