{"gene":"PTGIR","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2010,"finding":"PGI2-IP (PTGIR) signaling promotes Th1 differentiation through a cAMP-protein kinase A pathway. IP-deficient mice showed decreased contact hypersensitivity, reduced IFN-γ production, and smaller T-bet+ T cell subset. In vitro Th1 differentiation was enhanced by an IP agonist, and this enhancement was nullified by a PKA inhibitor. PGI synthase was detected in dendritic cells and IP in T cells, suggesting PGI2 produced by dendritic cells acts on IP in T cells.","method":"IP-deficient mouse model (contact hypersensitivity), in vitro Th1 differentiation assay with IP agonist and PKA inhibitor, quantitative real-time PCR for cell-type expression","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO phenotype replicated in vitro with pharmacological rescue using PKA inhibitor, multiple orthogonal methods","pmids":["20400695"],"is_preprint":false},{"year":2025,"finding":"PTGIR is a NRF2-dependent cell-intrinsic regulator of CD8+ T cell exhaustion. NRF2 (activated by KEAP1 deletion) upregulates PTGIR expression in CD8+ T cells. PTGIR signaling impairs T cell metabolism and cytokine production while inducing transcriptional features of exhaustion. Silencing PTGIR expression enhances IFN-γ and granzyme production and limits terminally exhausted (PD-1+TIM-3+) CD8+ T cell development in chronic infection and cancer models.","method":"Conditional KEAP1 deletion in CD8+ T cells, PTGIR silencing, transcriptomic profiling, chronic infection and tumor challenge models, cytokine production assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic manipulation (KEAP1 KO and PTGIR silencing) with multiple functional readouts replicated across chronic infection and cancer models","pmids":["40579556"],"is_preprint":false},{"year":2024,"finding":"PTGIR is an NRF2-regulated immune checkpoint linking oxidative stress to CD8+ T cell dysfunction. KEAP1 deletion promotes glutathione production but accelerates terminal CD8+ T cell exhaustion. PTGIR was identified as the downstream NRF2-regulated effector; silencing PTGIR restored anti-tumor function of KEAP1-deficient T cells and reduced terminal exhaustion in chronic infection.","method":"Conditional KEAP1 deletion, PTGIR silencing, transcriptional profiling, chronic infection and tumor models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint with genetic manipulation and multiple readouts but not yet peer-reviewed; largely corroborated by the published companion paper (PMID:40579556)","pmids":["38979360"],"is_preprint":true},{"year":2006,"finding":"PTGIR (IP receptor) mediates PGI2-dependent pain and inflammation. IP receptor-deficient mice showed 91% reduction in arthritis score in collagen-antibody induced arthritis. A selective IP antagonist reduced pain in a rat osteoarthritis model with efficacy approaching that of diclofenac. These data establish PGI2 as involved in development of chronic inflammation via IP signaling.","method":"IP receptor-deficient mice (genetic KO), selective IP antagonist pharmacology in rat OA model (monoiodoacetate injection) and mouse collagen-antibody induced arthritis model","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and pharmacological antagonist in two independent disease models with defined phenotypic readouts","pmids":["16973887"],"is_preprint":false},{"year":2021,"finding":"Rare loss-of-function (LoF) mutations in PTGIR are enriched in fibromuscular dysplasia (FMD). LoF variants Q163X and P17RfsX6, and missense variant L67P identified in FMD/SCAD patients, severely impaired hIP receptor function and/or protein expression when characterized by transient overexpression in human cells. The R212C polymorphism was previously shown to be dysfunctional, and additional LoF alleles were found in FMD patients by burden testing.","method":"Exome and targeted sequencing, burden testing against gnomAD controls, transient overexpression in human cells to characterize variant signaling and protein expression","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional in vitro characterization of multiple loss-of-function variants with signaling and expression assays, combined with human genetic enrichment analysis","pmids":["32531060"],"is_preprint":false},{"year":2008,"finding":"The PTGIR missense polymorphism R212C located in the third cytoplasmic loop is dysfunctional when examined in an in vitro overexpression system, and is associated with intimal hyperplasia in humans. Carriers of R212C had significantly higher intima-media thickness values. Synonymous polymorphisms V53V/S328S were associated with enhanced platelet activation markers (sP-selectin, 11-dehydro-TXB2) in DVT patients.","method":"In vitro overexpression system for functional receptor characterization, clinical biomarker measurements (intima-media thickness, sP-selectin, 11-dehydro-TXB2), PTGIR sequencing in DVT patients and controls","journal":"Pharmacogenetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional characterization of R212C variant combined with clinical phenotype association, single lab","pmids":["18551041"],"is_preprint":false},{"year":2022,"finding":"PTGIR mediates PGI2-triggered CD16- NK-cell differentiation. In vitro, PGI2 produced by PTGIS-overexpressing endometrial stromal cells triggered CD16- NK-cell differentiation through PTGIR in an ESC/NK-cell co-culture system. Treatment with the PTGIR antagonist RO1138452 partially rescued endometriosis progression in a rodent model.","method":"ESC/NK-cell co-culture system, PTGIR antagonist (RO1138452) treatment, ptgis-/- rodent model, adoptive transfer of fcgr3-/- NK cells","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-culture system with antagonist pharmacology and in vivo genetic model, single lab","pmids":["35781537"],"is_preprint":false},{"year":2023,"finding":"PTGIR activation on fibroblasts mediates antifibrotic effects of PGI2 in the kidney. PTGIR-deficient mice showed exacerbated renal fibrosis. Fibroblast/myofibroblast-specific deletion of PTGIR aggravated fibrosis. PGI2 analog or selective PTGIR agonist administered after acute injury ameliorated fibrosis via inhibition of fibroblast activation through PTGIR-mediated signaling. PTGIR deficiency blunted the protective effect of PGI2 analog.","method":"Ptgis-KO and Ptgir-KO mice, fibroblast-specific Ptgir conditional deletion, pharmacological PTGIR agonist/analog treatment, single-cell RNA-seq of human CKD kidneys","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (global and cell-type-specific KO) plus pharmacological rescue, with defined cellular mechanism (fibroblast activation inhibition)","pmids":["38062563"],"is_preprint":false},{"year":2025,"finding":"PTGIR signaling in intestinal fibroblasts inhibits YAP/TAZ pro-fibrotic activity, and this antifibrotic pathway is impaired in Crohn's disease. PTGIR transcription in fibroblasts is directly activated by p65 (NF-κB) upon TNF-α stimulation, while PTGIS is transcriptionally suppressed by TGF-β. PTGIR is expressed in intestinal fibroblasts but barely in epithelial cells. A PTGIR agonist inhibited YAP/TAZ profibrotic function in vitro and reversed intestinal fibrosis in a chronic colitis model in vivo.","method":"Dual luciferase reporter and Cut & Run assays for PTGIR/PTGIS transcriptional regulation, primary intestinal fibroblasts, chronic colitis mouse model, ELISA for serum PGI2 in CD patients","journal":"Journal of Crohn's & colitis","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct transcriptional regulatory mechanism (Cut & Run + reporter), cell-type-specific pathway placement (fibroblast YAP/TAZ), and in vivo pharmacological validation","pmids":["40390655"],"is_preprint":false},{"year":2029,"finding":"PTGIR signaling (via Gsα-coupled receptor activating adenylate cyclase) elevates cAMP, which activates PKA in platelets. Iloprost acting through PTGIR concentration-dependently inhibits platelet activation, aggregation, apoptosis, and in vivo thrombosis. PKA elevation by PTGIR signaling inhibits BAD dephosphorylation and reduces caspase-3 activity to retard platelet apoptosis. Low-dose iloprost (PTGIR agonism) elevates peripheral platelet counts in immune thrombocytopenia by inhibiting platelet apoptosis without affecting platelet function.","method":"Iloprost pharmacology in human and mouse platelets, PKA activity assays, Ca2+ measurements, FeCl3-induced thrombosis model, GPIbα antibody-induced ITP model, flow cytometry for apoptosis markers","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling cascade (PTGIR→Gsα→adenylate cyclase→cAMP→PKA→BAD/caspase-3) with multiple functional readouts, single lab","pmids":["39929746"],"is_preprint":false},{"year":2015,"finding":"In porcine endometrial cells, PTGIR activation by iloprost results in cAMP generation and increased expression of FGF-2 and VEGF164 mRNA in stromal (but not luminal epithelial) cells. PTGIR expression is upregulated during the peri-implantation period and is regulated by IL1β, IFNγ, and conceptus-derived factors but not estradiol.","method":"In vitro iloprost treatment of luminal epithelial and stromal cells, cAMP assay, qPCR for FGF-2 and VEGF164, endometrial tissue from cyclic and pregnant gilts","journal":"Theriogenology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional receptor activation assay (cAMP, angiogenic gene expression) in primary cells with cell-type specificity demonstrated, single lab","pmids":["26139576"],"is_preprint":false},{"year":2023,"finding":"In porcine endometrial endothelial cells, PTGIR activation by iloprost (PGI2 analogue) promotes angiogenesis-related processes including enhanced KDR, FGFR2, and ANGPT2 transcript abundance, increased cell proliferation (mediated by PI3K and mTOR activation), accelerated gap closure, and cell cycle progression. However, iloprost inhibited capillary-like structure formation.","method":"Iloprost treatment of porcine endometrial endothelial cells and G1410 cells, siRNA knockdown of PTGIS, proliferation assays, gap closure assay, cell cycle analysis, PI3K/mTOR pathway inhibitors","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays with siRNA knockdown and pharmacological pathway inhibition, single lab","pmids":["37644083"],"is_preprint":false},{"year":2010,"finding":"BEAS-2B human airway epithelial cells co-express two pharmacologically distinct prostacyclin receptors: the canonical IP receptor (PTGIR) and a novel 'IP2' subtype. siRNA directed against PTGIR blocked taprostene/iloprost-induced transcriptional responses (cAMP response element and glucocorticoid response element reporter activation) but failed to block suppression of CXCL9/CXCL10 chemokine output by taprostene and 15-deoxy-TIC, establishing that chemokine suppression is mediated by the novel IP2 receptor distinct from PTGIR.","method":"siRNA knockdown of PTGIR, HEK293 overexpression of recombinant hIP receptor, cAMP accumulation assays, luciferase reporter assays, pharmacological characterization with IP antagonist RO3244794","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown + recombinant receptor + pharmacological characterization establish mechanistic dissociation; single lab but multiple orthogonal methods","pmids":["21173040"],"is_preprint":false},{"year":2022,"finding":"PTGIR expression and signaling in human monocytes (THP-1) controls calprotectin (S100A8/S100A9) expression. Increasing PTGIR expression or stimulating PTGIR signaling increased calprotectin expression in THP-1 and hiPSC-derived monocytes; knockdown or inhibition of PTGIR decreased calprotectin expression. PTGIR-mediated calprotectin regulation is dependent on signaling via adenylate cyclase and STAT3.","method":"Lentiviral PTGIR overexpression in THP-1, siRNA knockdown, PTGIR agonist/antagonist pharmacology, hiPSC-derived monocyte validation, RNA-seq, adenylate cyclase and STAT3 pathway inhibitors","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function and loss-of-function with pharmacological rescue, validated in primary human iPSC-derived cells, defined signaling pathway (adenylate cyclase/STAT3), multiple orthogonal methods","pmids":["36155972"],"is_preprint":false},{"year":2014,"finding":"High-throughput error-prone PCR mutagenesis of the hIP receptor (PTGIR) identified 18 mutants expressed at the cell surface with impaired receptor function, mapping to 36 distinct residues including several in transmembrane domains. This established structure-function relationships for hIP receptor expression and signaling.","method":"Error-prone PCR mutagenesis library of >4000 hIP receptor mutants, next-generation sequencing for library validation, cell-surface expression assays, functional signaling assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional characterization; comprehensive but focused on identification rather than mechanism of individual residues","pmids":["24886841"],"is_preprint":false},{"year":2020,"finding":"PGI2 inhibits Brucella internalization into macrophages via PTGIR signaling, which leads to downregulation of F-actin polymerization and p38α MAPK activity. The PGI2 analogue selexipag acting through PTGIR suppressed immune responses and reduced bacterial burden in Brucella-challenged mice.","method":"Bone marrow-derived macrophage and RAW264.7 infection assays, selexipag (PTGIR agonist) pharmacology, F-actin polymerization and p38α MAPK activity measurements, in vivo mouse challenge","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling mechanism (PTGIR→F-actin/p38α MAPK) with in vitro and in vivo validation, single lab","pmids":["33091457"],"is_preprint":false},{"year":2025,"finding":"CTRP7 reduces PTGIR expression in pulmonary artery smooth muscle cells through Rab5a-mediated receptor internalization, thereby diminishing responsiveness to selexipag (prostacyclin analogue). IL-6 upregulates CTRP7 in PASMCs (confirmed by chromatin immunoprecipitation). Silencing CTRP7 in pulmonary arteries of hypoxic PH mice via AAV restored PTGIR expression and improved selexipag responsiveness.","method":"Chromatin immunoprecipitation for IL-6 regulation of CTRP7, RNA-seq of PASMCs, PTGIR internalization assay via Rab5a pathway, AAV-mediated CTRP7 silencing in hypoxic PH mice, IL-6-R neutralizing antibody treatment","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-validated transcriptional regulation, defined endosomal internalization mechanism (Rab5a), in vivo AAV rescue experiment with functional pharmacological readout","pmids":["40504501"],"is_preprint":false},{"year":2015,"finding":"PTGIR gene expression in the human vasculature is transcriptionally regulated by factors responsive to cellular differentiation, estrogen, and low serum-cholesterol. PTGIR interacts with PDZK1 (a multi-PDZ-domain protein essential for reverse-cholesterol transport and endothelialization) and with IKEPP (intestinal and kidney enriched PDZ protein), interactions that impact PTGIR function in the vasculature.","method":"Transcriptional regulation studies (trans-acting factor identification), protein interaction studies with PDZK1 and IKEPP (from review summarizing primary experimental work)","journal":"Prostaglandins & other lipid mediators","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review article summarizing primary work; methods for specific interactions not directly described in this abstract, cannot confirm experimental tier from abstract alone","pmids":["25936507"],"is_preprint":false},{"year":2014,"finding":"In HUVECs overexpressing PGI2 synthase (PGI2S), PTGIR protein is upregulated along with PKA and PKC, correlating with an anticoagulant phenotype. MAPK expression was not altered. These cells showed upregulation of ATIII and PLG and downregulation of FVIII.","method":"Lentiviral overexpression of PGI2S in HUVECs, qRT-PCR and western blotting for PTGIR, PKA, PKC, MAPK; ELISA for coagulation factors","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect measurement (PGI2S overexpression rather than PTGIR manipulation), single correlation, single lab","pmids":["24557578"],"is_preprint":false},{"year":1995,"finding":"The human PTGIR gene was chromosomally mapped to chromosome 19q13.3 using in situ hybridization.","method":"Chromosomal in situ hybridization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — direct cytogenetic mapping, replicated for multiple prostanoid receptor family members in same study","pmids":["7759114"],"is_preprint":false}],"current_model":"PTGIR encodes the Gs-coupled prostacyclin (PGI2) IP receptor that signals primarily through adenylate cyclase/cAMP/PKA to mediate vasodilation, inhibit platelet activation and apoptosis, suppress fibroblast activation (antifibrotic via YAP/TAZ inhibition), promote Th1 T cell differentiation, and drive CD8+ T cell exhaustion downstream of NRF2; receptor expression is regulated transcriptionally by NF-κB/p65, estrogen, and cholesterol, and post-translationally by CTRP7/Rab5a-mediated internalization, while loss-of-function variants in the third cytoplasmic loop (e.g., R212C) impair receptor signaling and associate with vascular pathologies including fibromuscular dysplasia."},"narrative":{"mechanistic_narrative":"PTGIR encodes the prostacyclin (PGI2/IP) receptor, a Gsα-coupled GPCR that signals through adenylate cyclase to raise cAMP and activate PKA, a cascade directly demonstrated in platelets where PTGIR agonism inhibits activation, aggregation, and apoptosis by blocking BAD dephosphorylation and reducing caspase-3 activity [PMID:39929746]. Across cell types this cAMP/PKA axis is repurposed: in fibroblasts PTGIR activation is antifibrotic, inhibiting fibroblast activation and YAP/TAZ pro-fibrotic transcriptional output, with genetic and pharmacological evidence in renal and intestinal fibrosis [PMID:38062563, PMID:40390655]; in monocytes PTGIR controls calprotectin (S100A8/S100A9) expression via adenylate cyclase and STAT3 [PMID:36155972]. PTGIR also shapes immunity, promoting Th1 differentiation through cAMP/PKA [PMID:20400695] and acting as an NRF2-induced cell-intrinsic driver of CD8+ T cell exhaustion that limits anti-tumor and anti-viral effector function [PMID:40579556]. Receptor abundance is set by transcriptional inputs—direct NF-κB/p65 activation of PTGIR upon TNF-α stimulation [PMID:40390655]—and by CTRP7/Rab5a-mediated internalization that desensitizes pulmonary artery smooth muscle cells to prostacyclin analogues [PMID:40504501]. Rare loss-of-function and missense variants, including R212C in the third cytoplasmic loop, impair receptor signaling and are enriched in fibromuscular dysplasia and associated with intimal hyperplasia [PMID:32531060, PMID:18551041].","teleology":[{"year":2008,"claim":"Established that natural PTGIR coding variants alter receptor function and link to human vascular disease, defining a structure-function-pathology axis for the receptor.","evidence":"In vitro overexpression characterization of the R212C third-cytoplasmic-loop variant plus clinical biomarker association in DVT/intimal hyperplasia","pmids":["18551041"],"confidence":"Medium","gaps":["Single lab; causality between R212C and intimal hyperplasia is associative","Mechanism by which the cytoplasmic-loop substitution disrupts Gs coupling not resolved"]},{"year":2010,"claim":"Answered whether PTGIR has a cell-intrinsic role in adaptive immunity, showing it promotes Th1 differentiation via cAMP/PKA rather than acting only on vasculature.","evidence":"IP-deficient mice in contact hypersensitivity plus in vitro Th1 assays with IP agonist and PKA inhibitor rescue","pmids":["20400695"],"confidence":"High","gaps":["Downstream transcriptional targets of PKA driving T-bet induction not defined","Direct PGI2 source-to-receptor handoff (DC to T cell) inferred from expression, not lineage tracing"]},{"year":2014,"claim":"Systematically mapped residues required for surface expression versus signaling, distinguishing receptor folding/trafficking determinants from coupling determinants.","evidence":"Error-prone PCR mutagenesis library of >4000 hIP mutants with NGS validation, surface-expression and functional assays","pmids":["24886841"],"confidence":"Medium","gaps":["Individual residue mechanisms not dissected","No structural model linking mutated residues to ligand binding or G-protein interface"]},{"year":2020,"claim":"Extended PTGIR signaling to innate antimicrobial control by linking the receptor to cytoskeletal and MAPK regulation of pathogen uptake.","evidence":"Macrophage Brucella internalization assays with selexipag, F-actin and p38α MAPK readouts, in vivo mouse challenge","pmids":["33091457"],"confidence":"Medium","gaps":["Connection between cAMP/PKA and F-actin/p38α not established","Single lab"]},{"year":2021,"claim":"Provided human genetic evidence that PTGIR loss-of-function causes vascular pathology, elevating prior variant associations to disease enrichment.","evidence":"Exome/targeted sequencing with burden testing against gnomAD plus transient-overexpression functional characterization of Q163X, P17RfsX6, L67P variants in FMD/SCAD patients","pmids":["32531060"],"confidence":"High","gaps":["Tissue/cell type in which receptor loss drives FMD not pinpointed","Functional assays performed in heterologous overexpression, not patient vessels"]},{"year":2022,"claim":"Defined a defined intracellular signaling route (adenylate cyclase/STAT3) by which PTGIR controls a specific inflammatory output in human monocytes.","evidence":"Lentiviral overexpression and siRNA knockdown in THP-1 and hiPSC-derived monocytes with pathway inhibitors and RNA-seq","pmids":["36155972"],"confidence":"High","gaps":["How adenylate cyclase signaling converges on STAT3 not mechanistically resolved","In vivo relevance of monocyte calprotectin regulation untested"]},{"year":2023,"claim":"Established PTGIR as an antifibrotic receptor acting on fibroblasts, defining the cellular target of prostacyclin's protective effect in fibrosis.","evidence":"Global, fibroblast-specific Ptgir-KO and Ptgis-KO mice with pharmacological agonist rescue and human CKD scRNA-seq","pmids":["38062563"],"confidence":"High","gaps":["Downstream transcriptional program suppressing fibroblast activation not defined here","Whether the effect generalizes beyond kidney addressed only later"]},{"year":2024,"claim":"Identified PTGIR as the NRF2-regulated effector linking oxidative-stress signaling to CD8+ T cell exhaustion, nominating it as an immune checkpoint.","evidence":"Conditional KEAP1 deletion and PTGIR silencing with transcriptional profiling in chronic infection and tumor models (preprint)","pmids":["38979360"],"confidence":"Medium","gaps":["Preprint; corroborated by companion paper but key claims awaited peer review","How PTGIR signaling reprograms T cell metabolism toward exhaustion not detailed"]},{"year":2025,"claim":"Confirmed PTGIR as a cell-intrinsic, NRF2-dependent regulator of CD8+ T cell exhaustion whose silencing restores effector function.","evidence":"KEAP1 deletion and PTGIR silencing with cytokine assays across chronic infection and cancer models","pmids":["40579556"],"confidence":"High","gaps":["Endogenous PGI2 source acting on exhausting T cells in vivo not identified","Whether PTGIR blockade synergizes with existing checkpoint therapy untested here"]},{"year":2025,"claim":"Resolved the transcriptional control of PTGIR and its antifibrotic mechanism in fibroblasts, placing the receptor in an NF-κB-induced YAP/TAZ-inhibitory pathway disrupted in disease.","evidence":"Dual-luciferase and Cut&Run for p65-driven PTGIR transcription, primary intestinal fibroblasts, chronic colitis model, patient serum PGI2","pmids":["40390655"],"confidence":"High","gaps":["Mechanistic link between PTGIR/cAMP signaling and YAP/TAZ phosphorylation not detailed","Reconciliation of NF-κB-driven PTGIR with TGF-β-suppressed PTGIS in vivo incomplete"]},{"year":2025,"claim":"Demonstrated post-translational control of PTGIR via CTRP7/Rab5a-mediated internalization, explaining loss of prostacyclin-analogue responsiveness in pulmonary hypertension.","evidence":"ChIP for IL-6/CTRP7, Rab5a internalization assay in PASMCs, AAV CTRP7 silencing in hypoxic PH mice with pharmacological readout","pmids":["40504501"],"confidence":"High","gaps":["Structural basis of CTRP7-PTGIR engagement not defined","Whether this internalization route operates in non-pulmonary vasculature unknown"]},{"year":null,"claim":"How a single Gs/cAMP/PKA receptor produces opposing cell-type-specific outcomes—antifibrotic and anti-platelet protection versus pro-exhaustion immunosuppression—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for context-dependent PTGIR signaling output","Structural/biophysical basis of receptor coupling not established","Endogenous PGI2 sources for each downstream context not all defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,0,13]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[14,16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,13,15]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[9]}],"complexes":[],"partners":["PDZK1","IKEPP","CTRP7","RAB5A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43119","full_name":"Prostacyclin receptor","aliases":["Prostaglandin I2 receptor","PGI receptor","PGI2 receptor","Prostanoid IP receptor"],"length_aa":386,"mass_kda":41.0,"function":"Receptor for prostacyclin (prostaglandin I2 or PGI2). The activity of this receptor is mediated by G(s) proteins which activate adenylate cyclase","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P43119/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTGIR","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTGIR","total_profiled":1310},"omim":[{"mim_id":"617828","title":"ZINC FINGER HOMEOBOX 2; ZFHX2","url":"https://www.omim.org/entry/617828"},{"mim_id":"600022","title":"PROSTAGLANDIN I2 RECEPTOR; PTGIR","url":"https://www.omim.org/entry/600022"},{"mim_id":"147430","title":"MARSILI SYNDROME; MARSIS","url":"https://www.omim.org/entry/147430"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":72.9},{"tissue":"lung","ntpm":55.0}],"url":"https://www.proteinatlas.org/search/PTGIR"},"hgnc":{"alias_symbol":["IP"],"prev_symbol":[]},"alphafold":{"accession":"P43119","domains":[{"cath_id":"1.20.1070.10","chopping":"18-219_234-311","consensus_level":"high","plddt":87.667,"start":18,"end":311}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43119","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43119-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43119-F1-predicted_aligned_error_v6.png","plddt_mean":76.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTGIR","jax_strain_url":"https://www.jax.org/strain/search?query=PTGIR"},"sequence":{"accession":"P43119","fasta_url":"https://rest.uniprot.org/uniprotkb/P43119.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43119/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43119"}},"corpus_meta":[{"pmid":"35717322","id":"PMC_35717322","title":"Comprehensive 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(PTGIR) signaling promotes Th1 differentiation through a cAMP-protein kinase A pathway. IP-deficient mice showed decreased contact hypersensitivity, reduced IFN-γ production, and smaller T-bet+ T cell subset. In vitro Th1 differentiation was enhanced by an IP agonist, and this enhancement was nullified by a PKA inhibitor. PGI synthase was detected in dendritic cells and IP in T cells, suggesting PGI2 produced by dendritic cells acts on IP in T cells.\",\n      \"method\": \"IP-deficient mouse model (contact hypersensitivity), in vitro Th1 differentiation assay with IP agonist and PKA inhibitor, quantitative real-time PCR for cell-type expression\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO phenotype replicated in vitro with pharmacological rescue using PKA inhibitor, multiple orthogonal methods\",\n      \"pmids\": [\"20400695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTGIR is a NRF2-dependent cell-intrinsic regulator of CD8+ T cell exhaustion. NRF2 (activated by KEAP1 deletion) upregulates PTGIR expression in CD8+ T cells. PTGIR signaling impairs T cell metabolism and cytokine production while inducing transcriptional features of exhaustion. Silencing PTGIR expression enhances IFN-γ and granzyme production and limits terminally exhausted (PD-1+TIM-3+) CD8+ T cell development in chronic infection and cancer models.\",\n      \"method\": \"Conditional KEAP1 deletion in CD8+ T cells, PTGIR silencing, transcriptomic profiling, chronic infection and tumor challenge models, cytokine production assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic manipulation (KEAP1 KO and PTGIR silencing) with multiple functional readouts replicated across chronic infection and cancer models\",\n      \"pmids\": [\"40579556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTGIR is an NRF2-regulated immune checkpoint linking oxidative stress to CD8+ T cell dysfunction. KEAP1 deletion promotes glutathione production but accelerates terminal CD8+ T cell exhaustion. PTGIR was identified as the downstream NRF2-regulated effector; silencing PTGIR restored anti-tumor function of KEAP1-deficient T cells and reduced terminal exhaustion in chronic infection.\",\n      \"method\": \"Conditional KEAP1 deletion, PTGIR silencing, transcriptional profiling, chronic infection and tumor models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint with genetic manipulation and multiple readouts but not yet peer-reviewed; largely corroborated by the published companion paper (PMID:40579556)\",\n      \"pmids\": [\"38979360\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PTGIR (IP receptor) mediates PGI2-dependent pain and inflammation. IP receptor-deficient mice showed 91% reduction in arthritis score in collagen-antibody induced arthritis. A selective IP antagonist reduced pain in a rat osteoarthritis model with efficacy approaching that of diclofenac. These data establish PGI2 as involved in development of chronic inflammation via IP signaling.\",\n      \"method\": \"IP receptor-deficient mice (genetic KO), selective IP antagonist pharmacology in rat OA model (monoiodoacetate injection) and mouse collagen-antibody induced arthritis model\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and pharmacological antagonist in two independent disease models with defined phenotypic readouts\",\n      \"pmids\": [\"16973887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rare loss-of-function (LoF) mutations in PTGIR are enriched in fibromuscular dysplasia (FMD). LoF variants Q163X and P17RfsX6, and missense variant L67P identified in FMD/SCAD patients, severely impaired hIP receptor function and/or protein expression when characterized by transient overexpression in human cells. The R212C polymorphism was previously shown to be dysfunctional, and additional LoF alleles were found in FMD patients by burden testing.\",\n      \"method\": \"Exome and targeted sequencing, burden testing against gnomAD controls, transient overexpression in human cells to characterize variant signaling and protein expression\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional in vitro characterization of multiple loss-of-function variants with signaling and expression assays, combined with human genetic enrichment analysis\",\n      \"pmids\": [\"32531060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The PTGIR missense polymorphism R212C located in the third cytoplasmic loop is dysfunctional when examined in an in vitro overexpression system, and is associated with intimal hyperplasia in humans. Carriers of R212C had significantly higher intima-media thickness values. Synonymous polymorphisms V53V/S328S were associated with enhanced platelet activation markers (sP-selectin, 11-dehydro-TXB2) in DVT patients.\",\n      \"method\": \"In vitro overexpression system for functional receptor characterization, clinical biomarker measurements (intima-media thickness, sP-selectin, 11-dehydro-TXB2), PTGIR sequencing in DVT patients and controls\",\n      \"journal\": \"Pharmacogenetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional characterization of R212C variant combined with clinical phenotype association, single lab\",\n      \"pmids\": [\"18551041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTGIR mediates PGI2-triggered CD16- NK-cell differentiation. In vitro, PGI2 produced by PTGIS-overexpressing endometrial stromal cells triggered CD16- NK-cell differentiation through PTGIR in an ESC/NK-cell co-culture system. Treatment with the PTGIR antagonist RO1138452 partially rescued endometriosis progression in a rodent model.\",\n      \"method\": \"ESC/NK-cell co-culture system, PTGIR antagonist (RO1138452) treatment, ptgis-/- rodent model, adoptive transfer of fcgr3-/- NK cells\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-culture system with antagonist pharmacology and in vivo genetic model, single lab\",\n      \"pmids\": [\"35781537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTGIR activation on fibroblasts mediates antifibrotic effects of PGI2 in the kidney. PTGIR-deficient mice showed exacerbated renal fibrosis. Fibroblast/myofibroblast-specific deletion of PTGIR aggravated fibrosis. PGI2 analog or selective PTGIR agonist administered after acute injury ameliorated fibrosis via inhibition of fibroblast activation through PTGIR-mediated signaling. PTGIR deficiency blunted the protective effect of PGI2 analog.\",\n      \"method\": \"Ptgis-KO and Ptgir-KO mice, fibroblast-specific Ptgir conditional deletion, pharmacological PTGIR agonist/analog treatment, single-cell RNA-seq of human CKD kidneys\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (global and cell-type-specific KO) plus pharmacological rescue, with defined cellular mechanism (fibroblast activation inhibition)\",\n      \"pmids\": [\"38062563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTGIR signaling in intestinal fibroblasts inhibits YAP/TAZ pro-fibrotic activity, and this antifibrotic pathway is impaired in Crohn's disease. PTGIR transcription in fibroblasts is directly activated by p65 (NF-κB) upon TNF-α stimulation, while PTGIS is transcriptionally suppressed by TGF-β. PTGIR is expressed in intestinal fibroblasts but barely in epithelial cells. A PTGIR agonist inhibited YAP/TAZ profibrotic function in vitro and reversed intestinal fibrosis in a chronic colitis model in vivo.\",\n      \"method\": \"Dual luciferase reporter and Cut & Run assays for PTGIR/PTGIS transcriptional regulation, primary intestinal fibroblasts, chronic colitis mouse model, ELISA for serum PGI2 in CD patients\",\n      \"journal\": \"Journal of Crohn's & colitis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct transcriptional regulatory mechanism (Cut & Run + reporter), cell-type-specific pathway placement (fibroblast YAP/TAZ), and in vivo pharmacological validation\",\n      \"pmids\": [\"40390655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2029,\n      \"finding\": \"PTGIR signaling (via Gsα-coupled receptor activating adenylate cyclase) elevates cAMP, which activates PKA in platelets. Iloprost acting through PTGIR concentration-dependently inhibits platelet activation, aggregation, apoptosis, and in vivo thrombosis. PKA elevation by PTGIR signaling inhibits BAD dephosphorylation and reduces caspase-3 activity to retard platelet apoptosis. Low-dose iloprost (PTGIR agonism) elevates peripheral platelet counts in immune thrombocytopenia by inhibiting platelet apoptosis without affecting platelet function.\",\n      \"method\": \"Iloprost pharmacology in human and mouse platelets, PKA activity assays, Ca2+ measurements, FeCl3-induced thrombosis model, GPIbα antibody-induced ITP model, flow cytometry for apoptosis markers\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling cascade (PTGIR→Gsα→adenylate cyclase→cAMP→PKA→BAD/caspase-3) with multiple functional readouts, single lab\",\n      \"pmids\": [\"39929746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In porcine endometrial cells, PTGIR activation by iloprost results in cAMP generation and increased expression of FGF-2 and VEGF164 mRNA in stromal (but not luminal epithelial) cells. PTGIR expression is upregulated during the peri-implantation period and is regulated by IL1β, IFNγ, and conceptus-derived factors but not estradiol.\",\n      \"method\": \"In vitro iloprost treatment of luminal epithelial and stromal cells, cAMP assay, qPCR for FGF-2 and VEGF164, endometrial tissue from cyclic and pregnant gilts\",\n      \"journal\": \"Theriogenology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional receptor activation assay (cAMP, angiogenic gene expression) in primary cells with cell-type specificity demonstrated, single lab\",\n      \"pmids\": [\"26139576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In porcine endometrial endothelial cells, PTGIR activation by iloprost (PGI2 analogue) promotes angiogenesis-related processes including enhanced KDR, FGFR2, and ANGPT2 transcript abundance, increased cell proliferation (mediated by PI3K and mTOR activation), accelerated gap closure, and cell cycle progression. However, iloprost inhibited capillary-like structure formation.\",\n      \"method\": \"Iloprost treatment of porcine endometrial endothelial cells and G1410 cells, siRNA knockdown of PTGIS, proliferation assays, gap closure assay, cell cycle analysis, PI3K/mTOR pathway inhibitors\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays with siRNA knockdown and pharmacological pathway inhibition, single lab\",\n      \"pmids\": [\"37644083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BEAS-2B human airway epithelial cells co-express two pharmacologically distinct prostacyclin receptors: the canonical IP receptor (PTGIR) and a novel 'IP2' subtype. siRNA directed against PTGIR blocked taprostene/iloprost-induced transcriptional responses (cAMP response element and glucocorticoid response element reporter activation) but failed to block suppression of CXCL9/CXCL10 chemokine output by taprostene and 15-deoxy-TIC, establishing that chemokine suppression is mediated by the novel IP2 receptor distinct from PTGIR.\",\n      \"method\": \"siRNA knockdown of PTGIR, HEK293 overexpression of recombinant hIP receptor, cAMP accumulation assays, luciferase reporter assays, pharmacological characterization with IP antagonist RO3244794\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown + recombinant receptor + pharmacological characterization establish mechanistic dissociation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21173040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTGIR expression and signaling in human monocytes (THP-1) controls calprotectin (S100A8/S100A9) expression. Increasing PTGIR expression or stimulating PTGIR signaling increased calprotectin expression in THP-1 and hiPSC-derived monocytes; knockdown or inhibition of PTGIR decreased calprotectin expression. PTGIR-mediated calprotectin regulation is dependent on signaling via adenylate cyclase and STAT3.\",\n      \"method\": \"Lentiviral PTGIR overexpression in THP-1, siRNA knockdown, PTGIR agonist/antagonist pharmacology, hiPSC-derived monocyte validation, RNA-seq, adenylate cyclase and STAT3 pathway inhibitors\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function and loss-of-function with pharmacological rescue, validated in primary human iPSC-derived cells, defined signaling pathway (adenylate cyclase/STAT3), multiple orthogonal methods\",\n      \"pmids\": [\"36155972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"High-throughput error-prone PCR mutagenesis of the hIP receptor (PTGIR) identified 18 mutants expressed at the cell surface with impaired receptor function, mapping to 36 distinct residues including several in transmembrane domains. This established structure-function relationships for hIP receptor expression and signaling.\",\n      \"method\": \"Error-prone PCR mutagenesis library of >4000 hIP receptor mutants, next-generation sequencing for library validation, cell-surface expression assays, functional signaling assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional characterization; comprehensive but focused on identification rather than mechanism of individual residues\",\n      \"pmids\": [\"24886841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PGI2 inhibits Brucella internalization into macrophages via PTGIR signaling, which leads to downregulation of F-actin polymerization and p38α MAPK activity. The PGI2 analogue selexipag acting through PTGIR suppressed immune responses and reduced bacterial burden in Brucella-challenged mice.\",\n      \"method\": \"Bone marrow-derived macrophage and RAW264.7 infection assays, selexipag (PTGIR agonist) pharmacology, F-actin polymerization and p38α MAPK activity measurements, in vivo mouse challenge\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling mechanism (PTGIR→F-actin/p38α MAPK) with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"33091457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CTRP7 reduces PTGIR expression in pulmonary artery smooth muscle cells through Rab5a-mediated receptor internalization, thereby diminishing responsiveness to selexipag (prostacyclin analogue). IL-6 upregulates CTRP7 in PASMCs (confirmed by chromatin immunoprecipitation). Silencing CTRP7 in pulmonary arteries of hypoxic PH mice via AAV restored PTGIR expression and improved selexipag responsiveness.\",\n      \"method\": \"Chromatin immunoprecipitation for IL-6 regulation of CTRP7, RNA-seq of PASMCs, PTGIR internalization assay via Rab5a pathway, AAV-mediated CTRP7 silencing in hypoxic PH mice, IL-6-R neutralizing antibody treatment\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-validated transcriptional regulation, defined endosomal internalization mechanism (Rab5a), in vivo AAV rescue experiment with functional pharmacological readout\",\n      \"pmids\": [\"40504501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTGIR gene expression in the human vasculature is transcriptionally regulated by factors responsive to cellular differentiation, estrogen, and low serum-cholesterol. PTGIR interacts with PDZK1 (a multi-PDZ-domain protein essential for reverse-cholesterol transport and endothelialization) and with IKEPP (intestinal and kidney enriched PDZ protein), interactions that impact PTGIR function in the vasculature.\",\n      \"method\": \"Transcriptional regulation studies (trans-acting factor identification), protein interaction studies with PDZK1 and IKEPP (from review summarizing primary experimental work)\",\n      \"journal\": \"Prostaglandins & other lipid mediators\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review article summarizing primary work; methods for specific interactions not directly described in this abstract, cannot confirm experimental tier from abstract alone\",\n      \"pmids\": [\"25936507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In HUVECs overexpressing PGI2 synthase (PGI2S), PTGIR protein is upregulated along with PKA and PKC, correlating with an anticoagulant phenotype. MAPK expression was not altered. These cells showed upregulation of ATIII and PLG and downregulation of FVIII.\",\n      \"method\": \"Lentiviral overexpression of PGI2S in HUVECs, qRT-PCR and western blotting for PTGIR, PKA, PKC, MAPK; ELISA for coagulation factors\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect measurement (PGI2S overexpression rather than PTGIR manipulation), single correlation, single lab\",\n      \"pmids\": [\"24557578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human PTGIR gene was chromosomally mapped to chromosome 19q13.3 using in situ hybridization.\",\n      \"method\": \"Chromosomal in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct cytogenetic mapping, replicated for multiple prostanoid receptor family members in same study\",\n      \"pmids\": [\"7759114\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTGIR encodes the Gs-coupled prostacyclin (PGI2) IP receptor that signals primarily through adenylate cyclase/cAMP/PKA to mediate vasodilation, inhibit platelet activation and apoptosis, suppress fibroblast activation (antifibrotic via YAP/TAZ inhibition), promote Th1 T cell differentiation, and drive CD8+ T cell exhaustion downstream of NRF2; receptor expression is regulated transcriptionally by NF-κB/p65, estrogen, and cholesterol, and post-translationally by CTRP7/Rab5a-mediated internalization, while loss-of-function variants in the third cytoplasmic loop (e.g., R212C) impair receptor signaling and associate with vascular pathologies including fibromuscular dysplasia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTGIR encodes the prostacyclin (PGI2/IP) receptor, a Gsα-coupled GPCR that signals through adenylate cyclase to raise cAMP and activate PKA, a cascade directly demonstrated in platelets where PTGIR agonism inhibits activation, aggregation, and apoptosis by blocking BAD dephosphorylation and reducing caspase-3 activity [#9]. Across cell types this cAMP/PKA axis is repurposed: in fibroblasts PTGIR activation is antifibrotic, inhibiting fibroblast activation and YAP/TAZ pro-fibrotic transcriptional output, with genetic and pharmacological evidence in renal and intestinal fibrosis [#7, #8]; in monocytes PTGIR controls calprotectin (S100A8/S100A9) expression via adenylate cyclase and STAT3 [#13]. PTGIR also shapes immunity, promoting Th1 differentiation through cAMP/PKA [#0] and acting as an NRF2-induced cell-intrinsic driver of CD8+ T cell exhaustion that limits anti-tumor and anti-viral effector function [#1]. Receptor abundance is set by transcriptional inputs—direct NF-κB/p65 activation of PTGIR upon TNF-α stimulation [#8]—and by CTRP7/Rab5a-mediated internalization that desensitizes pulmonary artery smooth muscle cells to prostacyclin analogues [#16]. Rare loss-of-function and missense variants, including R212C in the third cytoplasmic loop, impair receptor signaling and are enriched in fibromuscular dysplasia and associated with intimal hyperplasia [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that natural PTGIR coding variants alter receptor function and link to human vascular disease, defining a structure-function-pathology axis for the receptor.\",\n      \"evidence\": \"In vitro overexpression characterization of the R212C third-cytoplasmic-loop variant plus clinical biomarker association in DVT/intimal hyperplasia\",\n      \"pmids\": [\"18551041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; causality between R212C and intimal hyperplasia is associative\", \"Mechanism by which the cytoplasmic-loop substitution disrupts Gs coupling not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Answered whether PTGIR has a cell-intrinsic role in adaptive immunity, showing it promotes Th1 differentiation via cAMP/PKA rather than acting only on vasculature.\",\n      \"evidence\": \"IP-deficient mice in contact hypersensitivity plus in vitro Th1 assays with IP agonist and PKA inhibitor rescue\",\n      \"pmids\": [\"20400695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional targets of PKA driving T-bet induction not defined\", \"Direct PGI2 source-to-receptor handoff (DC to T cell) inferred from expression, not lineage tracing\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Systematically mapped residues required for surface expression versus signaling, distinguishing receptor folding/trafficking determinants from coupling determinants.\",\n      \"evidence\": \"Error-prone PCR mutagenesis library of >4000 hIP mutants with NGS validation, surface-expression and functional assays\",\n      \"pmids\": [\"24886841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual residue mechanisms not dissected\", \"No structural model linking mutated residues to ligand binding or G-protein interface\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended PTGIR signaling to innate antimicrobial control by linking the receptor to cytoskeletal and MAPK regulation of pathogen uptake.\",\n      \"evidence\": \"Macrophage Brucella internalization assays with selexipag, F-actin and p38α MAPK readouts, in vivo mouse challenge\",\n      \"pmids\": [\"33091457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection between cAMP/PKA and F-actin/p38α not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided human genetic evidence that PTGIR loss-of-function causes vascular pathology, elevating prior variant associations to disease enrichment.\",\n      \"evidence\": \"Exome/targeted sequencing with burden testing against gnomAD plus transient-overexpression functional characterization of Q163X, P17RfsX6, L67P variants in FMD/SCAD patients\",\n      \"pmids\": [\"32531060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue/cell type in which receptor loss drives FMD not pinpointed\", \"Functional assays performed in heterologous overexpression, not patient vessels\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a defined intracellular signaling route (adenylate cyclase/STAT3) by which PTGIR controls a specific inflammatory output in human monocytes.\",\n      \"evidence\": \"Lentiviral overexpression and siRNA knockdown in THP-1 and hiPSC-derived monocytes with pathway inhibitors and RNA-seq\",\n      \"pmids\": [\"36155972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How adenylate cyclase signaling converges on STAT3 not mechanistically resolved\", \"In vivo relevance of monocyte calprotectin regulation untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established PTGIR as an antifibrotic receptor acting on fibroblasts, defining the cellular target of prostacyclin's protective effect in fibrosis.\",\n      \"evidence\": \"Global, fibroblast-specific Ptgir-KO and Ptgis-KO mice with pharmacological agonist rescue and human CKD scRNA-seq\",\n      \"pmids\": [\"38062563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional program suppressing fibroblast activation not defined here\", \"Whether the effect generalizes beyond kidney addressed only later\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified PTGIR as the NRF2-regulated effector linking oxidative-stress signaling to CD8+ T cell exhaustion, nominating it as an immune checkpoint.\",\n      \"evidence\": \"Conditional KEAP1 deletion and PTGIR silencing with transcriptional profiling in chronic infection and tumor models (preprint)\",\n      \"pmids\": [\"38979360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; corroborated by companion paper but key claims awaited peer review\", \"How PTGIR signaling reprograms T cell metabolism toward exhaustion not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed PTGIR as a cell-intrinsic, NRF2-dependent regulator of CD8+ T cell exhaustion whose silencing restores effector function.\",\n      \"evidence\": \"KEAP1 deletion and PTGIR silencing with cytokine assays across chronic infection and cancer models\",\n      \"pmids\": [\"40579556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous PGI2 source acting on exhausting T cells in vivo not identified\", \"Whether PTGIR blockade synergizes with existing checkpoint therapy untested here\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the transcriptional control of PTGIR and its antifibrotic mechanism in fibroblasts, placing the receptor in an NF-κB-induced YAP/TAZ-inhibitory pathway disrupted in disease.\",\n      \"evidence\": \"Dual-luciferase and Cut&Run for p65-driven PTGIR transcription, primary intestinal fibroblasts, chronic colitis model, patient serum PGI2\",\n      \"pmids\": [\"40390655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between PTGIR/cAMP signaling and YAP/TAZ phosphorylation not detailed\", \"Reconciliation of NF-κB-driven PTGIR with TGF-β-suppressed PTGIS in vivo incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated post-translational control of PTGIR via CTRP7/Rab5a-mediated internalization, explaining loss of prostacyclin-analogue responsiveness in pulmonary hypertension.\",\n      \"evidence\": \"ChIP for IL-6/CTRP7, Rab5a internalization assay in PASMCs, AAV CTRP7 silencing in hypoxic PH mice with pharmacological readout\",\n      \"pmids\": [\"40504501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CTRP7-PTGIR engagement not defined\", \"Whether this internalization route operates in non-pulmonary vasculature unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single Gs/cAMP/PKA receptor produces opposing cell-type-specific outcomes—antifibrotic and anti-platelet protection versus pro-exhaustion immunosuppression—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for context-dependent PTGIR signaling output\", \"Structural/biophysical basis of receptor coupling not established\", \"Endogenous PGI2 sources for each downstream context not all defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 0, 13]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 13, 15]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PDZK1\", \"IKEPP\", \"CTRP7\", \"RAB5A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}