{"gene":"PILRB","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2010,"finding":"PILRβ (PILRB) is an activating receptor expressed on myeloid cells that directly interacts with S. aureus; activation of PILRβ increases bacterial burden and promotes a pro-inflammatory cytokine response (elevated IL-1β, TNF-α, IL-6), while genetic deletion of Pilrb in mice improves bacterial clearance, reduces pro-inflammatory cytokines, and increases IFN-γ and IL-12 from bone marrow-derived macrophages stimulated with heat-killed S. aureus.","method":"Pilrb knockout mouse model, agonistic antibody activation, BMDM stimulation assay, cytokine measurement in BAL and serum","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular and in vivo phenotype, multiple orthogonal readouts across in vivo and in vitro experiments","pmids":["20065029"],"is_preprint":false},{"year":2012,"finding":"PILRβ is a DAP12-binding partner expressed on myeloid cells; in the absence of PILRβ signaling, antigen-presenting cells produce increased IL-27 (p28), which promotes IL-10 production in effector T cells, leading to dampened immunopathology and enhanced survival in Toxoplasma gondii infection models.","method":"Pilrb knockout mouse model, T. gondii infection challenge (chronic encephalitis and IBD models), cytokine measurement","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined in vivo phenotype and cytokine pathway placement across two infection models","pmids":["22479310"],"is_preprint":false},{"year":2012,"finding":"PILRβ is identified as a DAP12-binding partner, establishing that it signals through DAP12 as an activating receptor on myeloid cells; CD99 is a potential ligand expressed on epithelial cells.","method":"Receptor-ligand characterization reported in the context of Pilrb KO functional studies","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — binding partner identification cited in the same study as functional KO data, but direct binding assay details not provided in abstract","pmids":["22479310"],"is_preprint":false},{"year":2006,"finding":"PILRB encodes an activating paired immunoglobulin-like receptor at the 7q22 locus; mouse Pilrb1 ligand is Cd99, which participates in recruitment of T cells to inflamed tissue, establishing PILRB as an immune system regulator through a defined ligand interaction.","method":"Comparative genomic analysis, mRNA expression profiling across tissues and cell types","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 3 — ligand identification supported by mouse genetic data cited in the paper, but binding mechanism not reconstituted in this study","pmids":["16926269"],"is_preprint":false},{"year":2024,"finding":"PILRB promotes gastric cancer tumorigenesis by binding IRS4 and recruiting the deubiquitinase OTUB1 to IRS4, relieving K48-linked ubiquitination of IRS4 and protecting it from proteasomal degradation, thereby hyperactivating the PI3K/AKT signaling pathway; PILRB also reprograms cholesterol metabolism by altering ABCA1 and SCARB1 expression levels.","method":"Co-immunoprecipitation, ubiquitination assay, loss-of-function and gain-of-function in vitro and in vivo (xenograft), protein stability assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding/Co-IP of PILRB-IRS4-OTUB1 complex, ubiquitination assay, in vitro and in vivo functional readouts with multiple orthogonal methods","pmids":["39227585"],"is_preprint":false},{"year":2025,"finding":"Loss of combined Pilrb1 and Pilrb2 (but not Pilra) in mice causes early-onset photoreceptor dysfunction measured by reduced ERG amplitudes from postnatal day 15; PILRB protein localizes specifically to the proximal part of photoreceptor outer segments, and Pilrb1/2-/- retinas show reduced expression of calcium-regulated phototransduction and synapse-associated proteins (GCAP1, GCAP2, PDE6b, AIPL1, PSD95, CTBP1), implicating dysregulation of calcium homeostasis as the mechanism.","method":"CRISPR germline deletion of Pilrb1/2 in mice, electroretinography, immunohistochemistry with cell-type-specific markers, PILRB immunostaining for localization","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — clean CRISPR KO with defined retinal phenotype, direct localization experiment with functional consequence, multiple orthogonal methods","pmids":["39532089"],"is_preprint":false},{"year":2016,"finding":"shRNA knockdown of Pilrb in Fanca-/- pre-leukemia stem cells improves leukemia-related survival without rescuing DNA damage response or genomic instability, placing PILRB in a signaling pathway parallel to DDR that promotes pre-LSC expansion and leukemia development.","method":"shRNA knockdown in Fanca-/- mouse hematopoietic stem cells, in vivo leukemia transplant assay, survival analysis","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis via KD with defined survival phenotype, but mechanism downstream of PILRB not characterized","pmids":["27568523"],"is_preprint":false},{"year":2021,"finding":"A causal 3'UTR variant at the PILRB locus alters PILRB mRNA abundance, nominated as an underlying causal variant for transcriptional changes associated with age-related macular degeneration, validated by endogenous allelic replacement.","method":"Massively parallel reporter assay (MPRAu) for 3'UTRs, endogenous allelic replacement (CRISPR)","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — endogenous allelic replacement confirms effect on abundance, but only regulatory (not protein-level mechanistic) finding","pmids":["34534445"],"is_preprint":false}],"current_model":"PILRB is a DAP12-associated activating receptor on myeloid cells that recognizes CD99 as a ligand; it modulates innate immune and inflammatory responses by promoting pro-inflammatory cytokine production and suppressing IL-27/IL-10 anti-inflammatory signaling, while in cancer cells it stabilizes IRS4 via OTUB1-mediated deubiquitination to hyperactivate PI3K/AKT signaling, and in photoreceptors it localizes to outer segments where it supports calcium homeostasis and phototransduction protein expression."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing PILRB as an activating receptor with a defined ligand: comparative genomics identified PILRB at 7q22 as the activating member of a paired receptor family, and mouse studies identified CD99 as its ligand, framing PILRB as an immune receptor with a concrete signaling partner.","evidence":"Comparative genomic analysis and mRNA profiling across tissues and cell types in mouse and human","pmids":["16926269"],"confidence":"Medium","gaps":["Direct biochemical reconstitution of PILRB–CD99 binding not performed in this study","Signaling adaptor for PILRB not yet demonstrated"]},{"year":2010,"claim":"Defining PILRB as a pro-inflammatory activating receptor on myeloid cells: Pilrb knockout mice showed improved S. aureus clearance with reduced IL-1β/TNF-α/IL-6 and increased IFN-γ/IL-12, establishing that PILRB skews macrophage responses toward pro-inflammatory cytokine production at the expense of protective antimicrobial immunity.","evidence":"Pilrb knockout mouse, agonistic antibody, BMDM stimulation, cytokine measurement in BAL and serum","pmids":["20065029"],"confidence":"High","gaps":["Downstream signaling cascade from PILRB to cytokine transcription not mapped","Whether PILRB directly binds S. aureus surface molecules or acts through indirect recognition not resolved"]},{"year":2012,"claim":"Connecting PILRB to the DAP12-dependent signaling axis and the IL-27/IL-10 regulatory circuit: loss of PILRB in T. gondii infection models revealed that PILRB normally suppresses IL-27 (p28) from APCs, which in turn limits IL-10 from T cells, establishing a specific immunoregulatory pathway downstream of DAP12.","evidence":"Pilrb knockout mice challenged with T. gondii in chronic encephalitis and IBD models, cytokine quantification","pmids":["22479310"],"confidence":"High","gaps":["Molecular mechanism by which DAP12-PILRB signaling represses IL-27 transcription unknown","Whether CD99 engagement is required for this pathway in vivo not tested"]},{"year":2016,"claim":"Implicating PILRB in leukemia stem cell expansion independent of DNA damage repair: knockdown of Pilrb in Fanca-/- pre-leukemia stem cells improved survival without correcting genomic instability, placing PILRB in a DDR-parallel pathway that promotes malignant stem cell expansion.","evidence":"shRNA knockdown in Fanca-/- hematopoietic stem cells, in vivo leukemia transplant and survival analysis","pmids":["27568523"],"confidence":"Medium","gaps":["Downstream effectors of PILRB signaling in LSCs not identified","Whether DAP12 is required for this leukemogenic role not tested","Knockdown rather than knockout; residual PILRB activity possible"]},{"year":2021,"claim":"Linking PILRB expression regulation to retinal disease: a causal 3′UTR variant at the PILRB locus was shown by endogenous allelic replacement to alter PILRB mRNA abundance, nominating PILRB as a functional gene underlying age-related macular degeneration risk.","evidence":"Massively parallel reporter assay for 3′UTRs, CRISPR endogenous allelic replacement","pmids":["34534445"],"confidence":"Medium","gaps":["Effect on PILRB protein level and retinal cell function not demonstrated","Causal path from altered PILRB abundance to AMD pathology not established"]},{"year":2024,"claim":"Revealing a non-immune oncogenic mechanism: PILRB was shown to stabilize IRS4 by recruiting OTUB1 to remove K48-linked ubiquitin chains, preventing proteasomal degradation and hyperactivating PI3K/AKT signaling in gastric cancer, demonstrating a direct scaffolding/adaptor function beyond classical immune receptor activity.","evidence":"Co-immunoprecipitation of PILRB–IRS4–OTUB1, ubiquitination assays, loss/gain-of-function in vitro and xenograft models","pmids":["39227585"],"confidence":"High","gaps":["Whether DAP12 is involved in this cancer signaling context unknown","Structural basis of PILRB–IRS4 and PILRB–OTUB1 interactions not resolved","Generalizability to cancers beyond gastric cancer not tested"]},{"year":2025,"claim":"Establishing a photoreceptor-intrinsic role: CRISPR deletion of Pilrb1/2 in mice caused early-onset photoreceptor dysfunction with loss of calcium-regulated phototransduction proteins, and PILRB was localized to outer segments, demonstrating a cell-autonomous sensory function distinct from its immune role.","evidence":"CRISPR germline deletion of Pilrb1/2, electroretinography, immunohistochemistry with cell-type markers","pmids":["39532089"],"confidence":"High","gaps":["Direct mechanism by which PILRB maintains calcium homeostasis in outer segments unknown","Whether PILRB signals through DAP12 or an alternative adaptor in photoreceptors not determined","Ligand for PILRB in the retinal context not identified"]},{"year":null,"claim":"The unifying signaling logic of PILRB across immune, cancer, and sensory contexts remains unresolved: whether DAP12-dependent and DAP12-independent pathways coexist, what ligands engage PILRB in non-immune tissues, and how PILRB's adaptor/scaffolding function for OTUB1–IRS4 relates to its canonical receptor activity are open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PILRB signaling complex exists","Tissue-specific adaptor usage (DAP12 vs. alternatives) not systematically assessed","Retinal and cancer ligands for PILRB not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,6]}],"complexes":[],"partners":["DAP12","CD99","IRS4","OTUB1"],"other_free_text":[]},"mechanistic_narrative":"PILRB encodes an activating paired immunoglobulin-like receptor that signals through the adaptor DAP12 and recognizes CD99 as a ligand, functioning broadly in innate immune regulation, cancer signaling, and photoreceptor physiology [PMID:22479310, PMID:16926269]. On myeloid cells, PILRB engagement promotes pro-inflammatory cytokine production (IL-1β, TNF-α, IL-6) while suppressing the IL-27/IL-10 anti-inflammatory axis; genetic deletion in mice improves bacterial clearance during S. aureus infection and limits immunopathology during Toxoplasma gondii infection [PMID:20065029, PMID:22479310]. In gastric cancer cells, PILRB stabilizes IRS4 by recruiting the deubiquitinase OTUB1, relieving K48-linked ubiquitination and thereby hyperactivating PI3K/AKT signaling and reprogramming cholesterol metabolism [PMID:39227585]. In photoreceptors, PILRB localizes to outer segments where its loss causes early-onset dysfunction with reduced expression of calcium-regulated phototransduction proteins, and a causal 3′UTR variant at the PILRB locus alters mRNA abundance and is associated with age-related macular degeneration [PMID:39532089, PMID:34534445]."},"prefetch_data":{"uniprot":{"accession":"Q9UKJ0","full_name":"Paired immunoglobulin-like type 2 receptor beta","aliases":["Activating receptor PILR-beta","Cell surface receptor FDFACT"],"length_aa":227,"mass_kda":25.5,"function":"Paired receptors consist of highly related activating and inhibitory receptors and are widely involved in the regulation of the immune system. PILRB is thought to act as a cellular signaling activating receptor that associates with ITAM-bearing adapter molecules on the cell surface","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9UKJ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PILRB","classification":"Not Classified","n_dependent_lines":19,"n_total_lines":1208,"dependency_fraction":0.015728476821192054},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PILRB","total_profiled":1310},"omim":[{"mim_id":"617012","title":"POLIOVIRUS RECEPTOR-RELATED IMMUNOGLOBULIN DOMAIN-CONTAINING PROTEIN; PVRIG","url":"https://www.omim.org/entry/617012"},{"mim_id":"616065","title":"PILR-ALPHA-ASSOCIATED NEURAL PROTEIN; PIANP","url":"https://www.omim.org/entry/616065"},{"mim_id":"605342","title":"PAIRED IMMUNOGLOBULIN-LIKE TYPE 2 RECEPTOR, BETA; PILRB","url":"https://www.omim.org/entry/605342"},{"mim_id":"605341","title":"PAIRED IMMUNOGLOBULIN-LIKE TYPE 2 RECEPTOR, ALPHA; PILRA","url":"https://www.omim.org/entry/605341"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PILRB"},"hgnc":{"alias_symbol":["FDFACT1","FDFACT2"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKJ0","domains":[{"cath_id":"2.60.40.10","chopping":"35-151","consensus_level":"high","plddt":96.9456,"start":35,"end":151}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKJ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKJ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKJ0-F1-predicted_aligned_error_v6.png","plddt_mean":80.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PILRB","jax_strain_url":"https://www.jax.org/strain/search?query=PILRB"},"sequence":{"accession":"Q9UKJ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKJ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKJ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKJ0"}},"corpus_meta":[{"pmid":"34534445","id":"PMC_34534445","title":"Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/34534445","citation_count":136,"is_preprint":false},{"pmid":"29263232","id":"PMC_29263232","title":"A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants.","date":"2017","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29263232","citation_count":117,"is_preprint":false},{"pmid":"27066552","id":"PMC_27066552","title":"Late-onset Alzheimer disease risk variants mark brain regulatory loci.","date":"2015","source":"Neurology. 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S. aureus.\",\n      \"method\": \"Pilrb knockout mouse model, agonistic antibody activation, BMDM stimulation assay, cytokine measurement in BAL and serum\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular and in vivo phenotype, multiple orthogonal readouts across in vivo and in vitro experiments\",\n      \"pmids\": [\"20065029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PILRβ is a DAP12-binding partner expressed on myeloid cells; in the absence of PILRβ signaling, antigen-presenting cells produce increased IL-27 (p28), which promotes IL-10 production in effector T cells, leading to dampened immunopathology and enhanced survival in Toxoplasma gondii infection models.\",\n      \"method\": \"Pilrb knockout mouse model, T. gondii infection challenge (chronic encephalitis and IBD models), cytokine measurement\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined in vivo phenotype and cytokine pathway placement across two infection models\",\n      \"pmids\": [\"22479310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PILRβ is identified as a DAP12-binding partner, establishing that it signals through DAP12 as an activating receptor on myeloid cells; CD99 is a potential ligand expressed on epithelial cells.\",\n      \"method\": \"Receptor-ligand characterization reported in the context of Pilrb KO functional studies\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — binding partner identification cited in the same study as functional KO data, but direct binding assay details not provided in abstract\",\n      \"pmids\": [\"22479310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PILRB encodes an activating paired immunoglobulin-like receptor at the 7q22 locus; mouse Pilrb1 ligand is Cd99, which participates in recruitment of T cells to inflamed tissue, establishing PILRB as an immune system regulator through a defined ligand interaction.\",\n      \"method\": \"Comparative genomic analysis, mRNA expression profiling across tissues and cell types\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — ligand identification supported by mouse genetic data cited in the paper, but binding mechanism not reconstituted in this study\",\n      \"pmids\": [\"16926269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PILRB promotes gastric cancer tumorigenesis by binding IRS4 and recruiting the deubiquitinase OTUB1 to IRS4, relieving K48-linked ubiquitination of IRS4 and protecting it from proteasomal degradation, thereby hyperactivating the PI3K/AKT signaling pathway; PILRB also reprograms cholesterol metabolism by altering ABCA1 and SCARB1 expression levels.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, loss-of-function and gain-of-function in vitro and in vivo (xenograft), protein stability assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding/Co-IP of PILRB-IRS4-OTUB1 complex, ubiquitination assay, in vitro and in vivo functional readouts with multiple orthogonal methods\",\n      \"pmids\": [\"39227585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of combined Pilrb1 and Pilrb2 (but not Pilra) in mice causes early-onset photoreceptor dysfunction measured by reduced ERG amplitudes from postnatal day 15; PILRB protein localizes specifically to the proximal part of photoreceptor outer segments, and Pilrb1/2-/- retinas show reduced expression of calcium-regulated phototransduction and synapse-associated proteins (GCAP1, GCAP2, PDE6b, AIPL1, PSD95, CTBP1), implicating dysregulation of calcium homeostasis as the mechanism.\",\n      \"method\": \"CRISPR germline deletion of Pilrb1/2 in mice, electroretinography, immunohistochemistry with cell-type-specific markers, PILRB immunostaining for localization\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean CRISPR KO with defined retinal phenotype, direct localization experiment with functional consequence, multiple orthogonal methods\",\n      \"pmids\": [\"39532089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"shRNA knockdown of Pilrb in Fanca-/- pre-leukemia stem cells improves leukemia-related survival without rescuing DNA damage response or genomic instability, placing PILRB in a signaling pathway parallel to DDR that promotes pre-LSC expansion and leukemia development.\",\n      \"method\": \"shRNA knockdown in Fanca-/- mouse hematopoietic stem cells, in vivo leukemia transplant assay, survival analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via KD with defined survival phenotype, but mechanism downstream of PILRB not characterized\",\n      \"pmids\": [\"27568523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A causal 3'UTR variant at the PILRB locus alters PILRB mRNA abundance, nominated as an underlying causal variant for transcriptional changes associated with age-related macular degeneration, validated by endogenous allelic replacement.\",\n      \"method\": \"Massively parallel reporter assay (MPRAu) for 3'UTRs, endogenous allelic replacement (CRISPR)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — endogenous allelic replacement confirms effect on abundance, but only regulatory (not protein-level mechanistic) finding\",\n      \"pmids\": [\"34534445\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PILRB is a DAP12-associated activating receptor on myeloid cells that recognizes CD99 as a ligand; it modulates innate immune and inflammatory responses by promoting pro-inflammatory cytokine production and suppressing IL-27/IL-10 anti-inflammatory signaling, while in cancer cells it stabilizes IRS4 via OTUB1-mediated deubiquitination to hyperactivate PI3K/AKT signaling, and in photoreceptors it localizes to outer segments where it supports calcium homeostasis and phototransduction protein expression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PILRB encodes an activating paired immunoglobulin-like receptor that signals through the adaptor DAP12 and recognizes CD99 as a ligand, functioning broadly in innate immune regulation, cancer signaling, and photoreceptor physiology [PMID:22479310, PMID:16926269]. On myeloid cells, PILRB engagement promotes pro-inflammatory cytokine production (IL-1β, TNF-α, IL-6) while suppressing the IL-27/IL-10 anti-inflammatory axis; genetic deletion in mice improves bacterial clearance during S. aureus infection and limits immunopathology during Toxoplasma gondii infection [PMID:20065029, PMID:22479310]. In gastric cancer cells, PILRB stabilizes IRS4 by recruiting the deubiquitinase OTUB1, relieving K48-linked ubiquitination and thereby hyperactivating PI3K/AKT signaling and reprogramming cholesterol metabolism [PMID:39227585]. In photoreceptors, PILRB localizes to outer segments where its loss causes early-onset dysfunction with reduced expression of calcium-regulated phototransduction proteins, and a causal 3′UTR variant at the PILRB locus alters mRNA abundance and is associated with age-related macular degeneration [PMID:39532089, PMID:34534445].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing PILRB as an activating receptor with a defined ligand: comparative genomics identified PILRB at 7q22 as the activating member of a paired receptor family, and mouse studies identified CD99 as its ligand, framing PILRB as an immune receptor with a concrete signaling partner.\",\n      \"evidence\": \"Comparative genomic analysis and mRNA profiling across tissues and cell types in mouse and human\",\n      \"pmids\": [\"16926269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical reconstitution of PILRB–CD99 binding not performed in this study\",\n        \"Signaling adaptor for PILRB not yet demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining PILRB as a pro-inflammatory activating receptor on myeloid cells: Pilrb knockout mice showed improved S. aureus clearance with reduced IL-1β/TNF-α/IL-6 and increased IFN-γ/IL-12, establishing that PILRB skews macrophage responses toward pro-inflammatory cytokine production at the expense of protective antimicrobial immunity.\",\n      \"evidence\": \"Pilrb knockout mouse, agonistic antibody, BMDM stimulation, cytokine measurement in BAL and serum\",\n      \"pmids\": [\"20065029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream signaling cascade from PILRB to cytokine transcription not mapped\",\n        \"Whether PILRB directly binds S. aureus surface molecules or acts through indirect recognition not resolved\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connecting PILRB to the DAP12-dependent signaling axis and the IL-27/IL-10 regulatory circuit: loss of PILRB in T. gondii infection models revealed that PILRB normally suppresses IL-27 (p28) from APCs, which in turn limits IL-10 from T cells, establishing a specific immunoregulatory pathway downstream of DAP12.\",\n      \"evidence\": \"Pilrb knockout mice challenged with T. gondii in chronic encephalitis and IBD models, cytokine quantification\",\n      \"pmids\": [\"22479310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which DAP12-PILRB signaling represses IL-27 transcription unknown\",\n        \"Whether CD99 engagement is required for this pathway in vivo not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Implicating PILRB in leukemia stem cell expansion independent of DNA damage repair: knockdown of Pilrb in Fanca-/- pre-leukemia stem cells improved survival without correcting genomic instability, placing PILRB in a DDR-parallel pathway that promotes malignant stem cell expansion.\",\n      \"evidence\": \"shRNA knockdown in Fanca-/- hematopoietic stem cells, in vivo leukemia transplant and survival analysis\",\n      \"pmids\": [\"27568523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream effectors of PILRB signaling in LSCs not identified\",\n        \"Whether DAP12 is required for this leukemogenic role not tested\",\n        \"Knockdown rather than knockout; residual PILRB activity possible\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking PILRB expression regulation to retinal disease: a causal 3′UTR variant at the PILRB locus was shown by endogenous allelic replacement to alter PILRB mRNA abundance, nominating PILRB as a functional gene underlying age-related macular degeneration risk.\",\n      \"evidence\": \"Massively parallel reporter assay for 3′UTRs, CRISPR endogenous allelic replacement\",\n      \"pmids\": [\"34534445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Effect on PILRB protein level and retinal cell function not demonstrated\",\n        \"Causal path from altered PILRB abundance to AMD pathology not established\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealing a non-immune oncogenic mechanism: PILRB was shown to stabilize IRS4 by recruiting OTUB1 to remove K48-linked ubiquitin chains, preventing proteasomal degradation and hyperactivating PI3K/AKT signaling in gastric cancer, demonstrating a direct scaffolding/adaptor function beyond classical immune receptor activity.\",\n      \"evidence\": \"Co-immunoprecipitation of PILRB–IRS4–OTUB1, ubiquitination assays, loss/gain-of-function in vitro and xenograft models\",\n      \"pmids\": [\"39227585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether DAP12 is involved in this cancer signaling context unknown\",\n        \"Structural basis of PILRB–IRS4 and PILRB–OTUB1 interactions not resolved\",\n        \"Generalizability to cancers beyond gastric cancer not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing a photoreceptor-intrinsic role: CRISPR deletion of Pilrb1/2 in mice caused early-onset photoreceptor dysfunction with loss of calcium-regulated phototransduction proteins, and PILRB was localized to outer segments, demonstrating a cell-autonomous sensory function distinct from its immune role.\",\n      \"evidence\": \"CRISPR germline deletion of Pilrb1/2, electroretinography, immunohistochemistry with cell-type markers\",\n      \"pmids\": [\"39532089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct mechanism by which PILRB maintains calcium homeostasis in outer segments unknown\",\n        \"Whether PILRB signals through DAP12 or an alternative adaptor in photoreceptors not determined\",\n        \"Ligand for PILRB in the retinal context not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying signaling logic of PILRB across immune, cancer, and sensory contexts remains unresolved: whether DAP12-dependent and DAP12-independent pathways coexist, what ligands engage PILRB in non-immune tissues, and how PILRB's adaptor/scaffolding function for OTUB1–IRS4 relates to its canonical receptor activity are open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of PILRB signaling complex exists\",\n        \"Tissue-specific adaptor usage (DAP12 vs. alternatives) not systematically assessed\",\n        \"Retinal and cancer ligands for PILRB not identified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DAP12\",\n      \"CD99\",\n      \"IRS4\",\n      \"OTUB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}