{"gene":"PPIB","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1991,"finding":"PPIB (cyclophilin B / SCYLP) encodes a secreted, glycosylated 21 kDa cyclosporin A-binding protein isolated from human milk. It possesses peptidyl-prolyl cis/trans isomerase (PPIase) activity that is inhibited by cyclosporin A, and is initially synthesized with a hydrophobic leader sequence targeting it for secretion, distinguishing it from cytosolic cyclophilin A.","method":"Protein purification from human milk, cDNA cloning from human T cells, recombinant expression in E. coli, PPIase activity assay, cyclosporin A inhibition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with purified recombinant protein, PPIase assay, inhibitor validation, and biochemical characterization of secretory signal in a single rigorous study","pmids":["2040592"],"is_preprint":false},{"year":2009,"finding":"PPIB encodes cyclophilin B (CyPB), which forms an intracellular collagen-modifying complex in the rough endoplasmic reticulum together with CRTAP and prolyl 3-hydroxylase 1 (P3H1/LEPRE1). This complex 3-hydroxylates proline at position 986 (P986) in the α1 chains of type I collagen. Loss-of-function mutations in PPIB cause autosomal-recessive osteogenesis imperfecta (OI) with decreased P986 3-hydroxylation, though hydroxylation is less severely reduced than in CRTAP or LEPRE1 deficiency, suggesting CyPB's cis-trans isomerase activity contributes independently to complex function.","method":"Human genetic analysis of OI families with PPIB mutations; biochemical quantification of collagen 3-prolyl hydroxylation levels in patient-derived cells; comparison with CRTAP- and LEPRE1-deficient patients","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and biochemical evidence from patient cells across multiple families, quantitative hydroxylation assays, replicated across independent OI studies","pmids":["19781681"],"is_preprint":false},{"year":2011,"finding":"PPIB-encoded cyclophilin B (CYPB) is required for efficient folding of the C-terminal propeptide of procollagen and for pro-α chain trimerization. In PPIB-deficient fibroblasts, proα1(I) chains are slow to assemble into trimers, overmodified procollagen accumulates in the rough endoplasmic reticulum (RER), and abnormal procollagen molecules abnormally bind protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1). This accumulation is greater than in CRTAP- or LEPRE1-deficient cells, placing CYPB as the earliest-acting component in the P3H1/CRTAP/CYPB complex during procollagen biosynthesis.","method":"Cultured dermal fibroblasts from OI patients with PPIB mutations; pulse-chase analysis of procollagen trimer assembly; co-immunoprecipitation of procollagen with PDI and P4H1; RER accumulation assessed by cell fractionation and imaging; comparison with CRTAP- and LEPRE1-deficient cells","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (pulse-chase, co-IP, fractionation) in patient-derived cells with mechanistic comparison across three gene-deficient backgrounds in a single rigorous study","pmids":["21282188"],"is_preprint":false},{"year":2012,"finding":"Overexpressed cyclophilin B (CypB/PPIB) is released extracellularly from hepatoma cells and binds to the cell-surface receptor CD147. This interaction activates the ERK intracellular signaling pathway and protects hepatoma cells against oxidative stress-induced apoptosis. The protective effect depends on the PPIase catalytic activity of CypB, as siRNA knockdown of CypB renders cells more vulnerable to ROS-mediated apoptosis.","method":"siRNA knockdown of CypB in human hepatoma cells; co-immunoprecipitation of secreted CypB with CD147; ERK phosphorylation assays; cell viability/apoptosis assays under oxidative stress; PPIase inhibitor studies","journal":"Apoptosis : an international journal on programmed cell death","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of CypB–CD147 interaction, functional rescue assays, and ERK pathway readout in a single lab with two orthogonal methods (co-IP + functional knockdown)","pmids":["22555451"],"is_preprint":false}],"current_model":"PPIB encodes cyclophilin B (CypB), an endoplasmic reticulum-resident peptidyl-prolyl cis/trans isomerase that (i) possesses cyclosporin A-sensitive PPIase activity and can be secreted via an N-terminal signal sequence, (ii) forms a trimeric complex with CRTAP and prolyl 3-hydroxylase 1 (P3H1) in the RER where it acts as the earliest-required factor for folding of the procollagen C-terminal propeptide and pro-α chain trimerization prior to 3-hydroxylation of Pro986 in type I collagen α1 chains, and (iii) when overexpressed and secreted, binds CD147 on the cell surface to activate ERK signaling and confer resistance to oxidative stress in a PPIase-activity-dependent manner; loss-of-function mutations cause autosomal-recessive osteogenesis imperfecta."},"narrative":{"mechanistic_narrative":"PPIB encodes cyclophilin B (CypB), a peptidyl-prolyl cis/trans isomerase synthesized with a hydrophobic leader sequence that targets it to the secretory pathway, with PPIase activity that is inhibited by cyclosporin A [PMID:2040592]. Within the rough endoplasmic reticulum, CypB assembles with CRTAP and prolyl 3-hydroxylase 1 (P3H1/LEPRE1) into a complex that 3-hydroxylates Pro986 in the α1 chains of type I collagen [PMID:19781681]. CypB is the earliest-acting component of this collagen-folding machinery: it is required for efficient folding of the procollagen C-terminal propeptide and for pro-α chain trimerization, and its loss causes slow trimer assembly, accumulation of overmodified procollagen in the RER, and aberrant association of procollagen with PDI and prolyl 4-hydroxylase 1 [PMID:21282188]. Loss-of-function PPIB mutations cause autosomal-recessive osteogenesis imperfecta [PMID:19781681]. Beyond its intracellular role, secreted CypB binds the cell-surface receptor CD147 to activate ERK signaling and protect cells from oxidative stress-induced apoptosis in a manner dependent on its PPIase activity [PMID:22555451].","teleology":[{"year":1991,"claim":"Established that PPIB encodes a distinct, secreted cyclophilin with bona fide enzymatic PPIase activity, defining it as a secretory-pathway isomerase rather than a cytosolic one.","evidence":"Protein purification from human milk, cDNA cloning, recombinant expression, PPIase and cyclosporin A inhibition assays","pmids":["2040592"],"confidence":"High","gaps":["Physiological substrates of the PPIase activity not identified","Subcellular site of action within the secretory pathway not resolved","No link to a biological process established yet"]},{"year":2009,"claim":"Connected CypB to collagen biosynthesis by placing it in a CRTAP/P3H1 complex that 3-hydroxylates Pro986 of type I collagen and showing its loss causes recessive osteogenesis imperfecta.","evidence":"Human genetic analysis of OI families plus biochemical quantification of collagen 3-prolyl hydroxylation in patient cells, compared to CRTAP/LEPRE1 deficiency","pmids":["19781681"],"confidence":"High","gaps":["Why hydroxylation is less reduced than in CRTAP/LEPRE1 deficiency not fully explained","Whether the isomerase contributes a function independent of hydroxylation not directly tested here"]},{"year":2011,"claim":"Resolved CypB's order of action, showing it is the earliest-required factor for procollagen C-propeptide folding and pro-α chain trimerization, upstream of hydroxylation.","evidence":"Pulse-chase trimer assembly, co-IP of procollagen with PDI/P4H1, and cell fractionation in PPIB-deficient patient fibroblasts versus CRTAP/LEPRE1 deficiency","pmids":["21282188"],"confidence":"High","gaps":["Direct enzymatic substrate prolines isomerized by CypB during folding not mapped","Structural basis of complex assembly not determined"]},{"year":2012,"claim":"Identified an extracellular signaling role for secreted CypB via CD147, linking its PPIase activity to ERK activation and oxidative stress survival.","evidence":"siRNA knockdown, co-IP of secreted CypB with CD147, ERK phosphorylation and apoptosis assays under oxidative stress in hepatoma cells","pmids":["22555451"],"confidence":"Medium","gaps":["Single-lab study using overexpression; physiological relevance of secreted CypB at endogenous levels unclear","Mechanism by which PPIase activity is required for CD147-ERK signaling not defined","No reciprocal validation across cell types"]},{"year":null,"claim":"How CypB's isomerase activity mechanistically drives procollagen folding versus its scaffolding role in the hydroxylation complex, and whether its extracellular CD147 signaling occurs under normal physiology, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the CypB/CRTAP/P3H1 complex","Substrate prolines isomerized during procollagen folding unmapped","Endogenous relevance of secreted CypB-CD147 axis untested in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2]}],"complexes":["P3H1/CRTAP/CypB collagen prolyl 3-hydroxylation complex"],"partners":["CRTAP","P3H1","PDI","P4H1","CD147"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23284","full_name":"Peptidyl-prolyl cis-trans isomerase B","aliases":["CYP-S1","Cyclophilin B","Rotamase B","S-cyclophilin","SCYLP"],"length_aa":216,"mass_kda":23.7,"function":"PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding","subcellular_location":"Endoplasmic reticulum lumen; Melanosome","url":"https://www.uniprot.org/uniprotkb/P23284/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPIB","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PPIB","total_profiled":1310},"omim":[{"mim_id":"615713","title":"ZINC FINGER MYND DOMAIN-CONTAINING PROTEIN 8; ZMYND8","url":"https://www.omim.org/entry/615713"},{"mim_id":"610968","title":"OSTEOGENESIS IMPERFECTA, TYPE XI; OI11","url":"https://www.omim.org/entry/610968"},{"mim_id":"610915","title":"OSTEOGENESIS IMPERFECTA, TYPE VIII; OI8","url":"https://www.omim.org/entry/610915"},{"mim_id":"610339","title":"PROLYL 3-HYDROXYLASE 1; P3H1","url":"https://www.omim.org/entry/610339"},{"mim_id":"607461","title":"DYMECLIN; DYM","url":"https://www.omim.org/entry/607461"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PPIB"},"hgnc":{"alias_symbol":["CYPB","OI9","PPIase","B","CYP-S1","SCYLP"],"prev_symbol":[]},"alphafold":{"accession":"P23284","domains":[{"cath_id":"-","chopping":"1-31","consensus_level":"medium","plddt":66.019,"start":1,"end":31},{"cath_id":"2.40.100.10","chopping":"32-210","consensus_level":"high","plddt":96.1858,"start":32,"end":210}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23284","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23284-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23284-F1-predicted_aligned_error_v6.png","plddt_mean":91.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPIB","jax_strain_url":"https://www.jax.org/strain/search?query=PPIB"},"sequence":{"accession":"P23284","fasta_url":"https://rest.uniprot.org/uniprotkb/P23284.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23284/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23284"}},"corpus_meta":[{"pmid":"7071593","id":"PMC_7071593","title":"The anatomy of A-, B-, and Z-DNA.","date":"1982","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7071593","citation_count":475,"is_preprint":false},{"pmid":"11168923","id":"PMC_11168923","title":"Transcription factor-kappa B (NF-kappa B) and renal disease.","date":"2001","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/11168923","citation_count":447,"is_preprint":false},{"pmid":"14758357","id":"PMC_14758357","title":"B cell receptor signal strength determines B cell fate.","date":"2004","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14758357","citation_count":440,"is_preprint":false},{"pmid":"1591006","id":"PMC_1591006","title":"Antigen receptors on B lymphocytes.","date":"1992","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1591006","citation_count":437,"is_preprint":false},{"pmid":"36774930","id":"PMC_36774930","title":"Hepatitis B.","date":"2023","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36774930","citation_count":429,"is_preprint":false},{"pmid":"10724453","id":"PMC_10724453","title":"B-chromosome evolution.","date":"2000","source":"Philosophical transactions of the Royal Society of London. 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Introduction.","date":"2001","source":"International reviews of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11913944","citation_count":23,"is_preprint":false},{"pmid":"12213328","id":"PMC_12213328","title":"Defective CD19-dependent signaling in B-1a and B-1b B lymphocyte subpopulations.","date":"2002","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12213328","citation_count":23,"is_preprint":false},{"pmid":"30323027","id":"PMC_30323027","title":"Peptidyl-Prolyl-cis/trans-Isomerases Mip and PpiB of Legionella pneumophila Contribute to Surface Translocation, Growth at Suboptimal Temperature, and Infection.","date":"2018","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/30323027","citation_count":22,"is_preprint":false},{"pmid":"11810224","id":"PMC_11810224","title":"The foldase CYPB is a component of the secretory pathway of Aspergillus niger and contains the endoplasmic reticulum retention signal HEEL.","date":"2001","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/11810224","citation_count":22,"is_preprint":false},{"pmid":"27306110","id":"PMC_27306110","title":"Cyclophilin PpiB is involved in motility and biofilm formation via its functional association with certain proteins.","date":"2016","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/27306110","citation_count":22,"is_preprint":false},{"pmid":"32455610","id":"PMC_32455610","title":"Genome Maintenance by DNA Helicase B.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/32455610","citation_count":21,"is_preprint":false},{"pmid":"26165513","id":"PMC_26165513","title":"Ibrutinib in B lymphoid malignancies.","date":"2015","source":"Expert opinion on pharmacotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/26165513","citation_count":21,"is_preprint":false},{"pmid":"35711430","id":"PMC_35711430","title":"Glycoprotein B Antibodies Completely Neutralize EBV Infection of B Cells.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35711430","citation_count":21,"is_preprint":false},{"pmid":"34576154","id":"PMC_34576154","title":"Exploiting B Cell Transfer for Cancer Therapy: Engineered B Cells to Eradicate Tumors.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34576154","citation_count":20,"is_preprint":false},{"pmid":"1418702","id":"PMC_1418702","title":"B-cell activation.","date":"1992","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1418702","citation_count":19,"is_preprint":false},{"pmid":"2015042","id":"PMC_2015042","title":"To B, or not to B: that is the question.","date":"1991","source":"Immunology today","url":"https://pubmed.ncbi.nlm.nih.gov/2015042","citation_count":19,"is_preprint":false},{"pmid":"12726991","id":"PMC_12726991","title":"Cathepsin B in osteoblasts.","date":"2003","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/12726991","citation_count":18,"is_preprint":false},{"pmid":"30779034","id":"PMC_30779034","title":"Stereotyped B Cell Receptor Immunoglobulins in B Cell Lymphomas.","date":"2019","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/30779034","citation_count":17,"is_preprint":false},{"pmid":"30104214","id":"PMC_30104214","title":"The Intracellular Cyclophilin PpiB Contributes to the Virulence of Staphylococcus aureus Independently of Its Peptidyl-Prolyl cis/trans Isomerase Activity.","date":"2018","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/30104214","citation_count":17,"is_preprint":false},{"pmid":"32391647","id":"PMC_32391647","title":"Hepatitis B virus-induced hyperactivation of B cells in chronic hepatitis B patients via TLR4.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32391647","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":42163,"output_tokens":2053,"usd":0.078642,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8352,"output_tokens":2112,"usd":0.04728,"stage2_stop_reason":"end_turn"},"total_usd":0.125922,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers specifically about PPIB (cyclophilin B / CypB / SCYLP / CYPB / OI9) - the human peptidyl-prolyl cis-trans isomerase B protein.\n\nRelevant papers:\n- [11] PMID:19781681 - PPIB mutations causing OI, complex with CRTAP/P3H1\n- [20] PMID:2040592 - Novel secreted cyclophilin-like protein (SCYLP) - this IS PPIB based on the alias SCYLP\n- [23] PMID:21282188 - PPIB mutations delay procollagen chain association\n- [29] PMID:15464605 - PPIB as reference gene (expression stability, not mechanistic)\n- [64] PMID:34943932 - Giardia PPIB triggers inflammasome (but this is Giardia's PPIB, not human PPIB)\n- [65] PMID:22555451 - CypB (CypB = PPIB alias) binding to CD147 in hepatoma cells\n- [89] PMID:11810224 - Aspergillus niger cypB - symbol collision, skip\n- [82] PMID:8022278 - Bacillus subtilis ppiB - symbol collision (bacterial), skip\n- [88] PMID:30323027 - Legionella PpiB - bacterial, skip\n- [90] PMID:27306110 - E. coli PpiB - bacterial, skip\n- [99] PMID:30104214 - Staphylococcus aureus PpiB - bacterial, skip\n\nPaper [64] describes Giardia's secreted PPIB acting on human macrophages - this is a foreign protein acting on host cells, not the human PPIB gene product mechanistically.\n\nPaper [29] is about expression stability - not mechanistic.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"PPIB (cyclophilin B / SCYLP) encodes a secreted, glycosylated 21 kDa cyclosporin A-binding protein isolated from human milk. It possesses peptidyl-prolyl cis/trans isomerase (PPIase) activity that is inhibited by cyclosporin A, and is initially synthesized with a hydrophobic leader sequence targeting it for secretion, distinguishing it from cytosolic cyclophilin A.\",\n      \"method\": \"Protein purification from human milk, cDNA cloning from human T cells, recombinant expression in E. coli, PPIase activity assay, cyclosporin A inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with purified recombinant protein, PPIase assay, inhibitor validation, and biochemical characterization of secretory signal in a single rigorous study\",\n      \"pmids\": [\"2040592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PPIB encodes cyclophilin B (CyPB), which forms an intracellular collagen-modifying complex in the rough endoplasmic reticulum together with CRTAP and prolyl 3-hydroxylase 1 (P3H1/LEPRE1). This complex 3-hydroxylates proline at position 986 (P986) in the α1 chains of type I collagen. Loss-of-function mutations in PPIB cause autosomal-recessive osteogenesis imperfecta (OI) with decreased P986 3-hydroxylation, though hydroxylation is less severely reduced than in CRTAP or LEPRE1 deficiency, suggesting CyPB's cis-trans isomerase activity contributes independently to complex function.\",\n      \"method\": \"Human genetic analysis of OI families with PPIB mutations; biochemical quantification of collagen 3-prolyl hydroxylation levels in patient-derived cells; comparison with CRTAP- and LEPRE1-deficient patients\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and biochemical evidence from patient cells across multiple families, quantitative hydroxylation assays, replicated across independent OI studies\",\n      \"pmids\": [\"19781681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PPIB-encoded cyclophilin B (CYPB) is required for efficient folding of the C-terminal propeptide of procollagen and for pro-α chain trimerization. In PPIB-deficient fibroblasts, proα1(I) chains are slow to assemble into trimers, overmodified procollagen accumulates in the rough endoplasmic reticulum (RER), and abnormal procollagen molecules abnormally bind protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1). This accumulation is greater than in CRTAP- or LEPRE1-deficient cells, placing CYPB as the earliest-acting component in the P3H1/CRTAP/CYPB complex during procollagen biosynthesis.\",\n      \"method\": \"Cultured dermal fibroblasts from OI patients with PPIB mutations; pulse-chase analysis of procollagen trimer assembly; co-immunoprecipitation of procollagen with PDI and P4H1; RER accumulation assessed by cell fractionation and imaging; comparison with CRTAP- and LEPRE1-deficient cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (pulse-chase, co-IP, fractionation) in patient-derived cells with mechanistic comparison across three gene-deficient backgrounds in a single rigorous study\",\n      \"pmids\": [\"21282188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Overexpressed cyclophilin B (CypB/PPIB) is released extracellularly from hepatoma cells and binds to the cell-surface receptor CD147. This interaction activates the ERK intracellular signaling pathway and protects hepatoma cells against oxidative stress-induced apoptosis. The protective effect depends on the PPIase catalytic activity of CypB, as siRNA knockdown of CypB renders cells more vulnerable to ROS-mediated apoptosis.\",\n      \"method\": \"siRNA knockdown of CypB in human hepatoma cells; co-immunoprecipitation of secreted CypB with CD147; ERK phosphorylation assays; cell viability/apoptosis assays under oxidative stress; PPIase inhibitor studies\",\n      \"journal\": \"Apoptosis : an international journal on programmed cell death\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of CypB–CD147 interaction, functional rescue assays, and ERK pathway readout in a single lab with two orthogonal methods (co-IP + functional knockdown)\",\n      \"pmids\": [\"22555451\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPIB encodes cyclophilin B (CypB), an endoplasmic reticulum-resident peptidyl-prolyl cis/trans isomerase that (i) possesses cyclosporin A-sensitive PPIase activity and can be secreted via an N-terminal signal sequence, (ii) forms a trimeric complex with CRTAP and prolyl 3-hydroxylase 1 (P3H1) in the RER where it acts as the earliest-required factor for folding of the procollagen C-terminal propeptide and pro-α chain trimerization prior to 3-hydroxylation of Pro986 in type I collagen α1 chains, and (iii) when overexpressed and secreted, binds CD147 on the cell surface to activate ERK signaling and confer resistance to oxidative stress in a PPIase-activity-dependent manner; loss-of-function mutations cause autosomal-recessive osteogenesis imperfecta.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPIB encodes cyclophilin B (CypB), a peptidyl-prolyl cis/trans isomerase synthesized with a hydrophobic leader sequence that targets it to the secretory pathway, with PPIase activity that is inhibited by cyclosporin A [#0]. Within the rough endoplasmic reticulum, CypB assembles with CRTAP and prolyl 3-hydroxylase 1 (P3H1/LEPRE1) into a complex that 3-hydroxylates Pro986 in the \\u03b11 chains of type I collagen [#1]. CypB is the earliest-acting component of this collagen-folding machinery: it is required for efficient folding of the procollagen C-terminal propeptide and for pro-\\u03b1 chain trimerization, and its loss causes slow trimer assembly, accumulation of overmodified procollagen in the RER, and aberrant association of procollagen with PDI and prolyl 4-hydroxylase 1 [#2]. Loss-of-function PPIB mutations cause autosomal-recessive osteogenesis imperfecta [#1]. Beyond its intracellular role, secreted CypB binds the cell-surface receptor CD147 to activate ERK signaling and protect cells from oxidative stress-induced apoptosis in a manner dependent on its PPIase activity [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that PPIB encodes a distinct, secreted cyclophilin with bona fide enzymatic PPIase activity, defining it as a secretory-pathway isomerase rather than a cytosolic one.\",\n      \"evidence\": \"Protein purification from human milk, cDNA cloning, recombinant expression, PPIase and cyclosporin A inhibition assays\",\n      \"pmids\": [\"2040592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological substrates of the PPIase activity not identified\",\n        \"Subcellular site of action within the secretory pathway not resolved\",\n        \"No link to a biological process established yet\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected CypB to collagen biosynthesis by placing it in a CRTAP/P3H1 complex that 3-hydroxylates Pro986 of type I collagen and showing its loss causes recessive osteogenesis imperfecta.\",\n      \"evidence\": \"Human genetic analysis of OI families plus biochemical quantification of collagen 3-prolyl hydroxylation in patient cells, compared to CRTAP/LEPRE1 deficiency\",\n      \"pmids\": [\"19781681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Why hydroxylation is less reduced than in CRTAP/LEPRE1 deficiency not fully explained\",\n        \"Whether the isomerase contributes a function independent of hydroxylation not directly tested here\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved CypB's order of action, showing it is the earliest-required factor for procollagen C-propeptide folding and pro-\\u03b1 chain trimerization, upstream of hydroxylation.\",\n      \"evidence\": \"Pulse-chase trimer assembly, co-IP of procollagen with PDI/P4H1, and cell fractionation in PPIB-deficient patient fibroblasts versus CRTAP/LEPRE1 deficiency\",\n      \"pmids\": [\"21282188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct enzymatic substrate prolines isomerized by CypB during folding not mapped\",\n        \"Structural basis of complex assembly not determined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified an extracellular signaling role for secreted CypB via CD147, linking its PPIase activity to ERK activation and oxidative stress survival.\",\n      \"evidence\": \"siRNA knockdown, co-IP of secreted CypB with CD147, ERK phosphorylation and apoptosis assays under oxidative stress in hepatoma cells\",\n      \"pmids\": [\"22555451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study using overexpression; physiological relevance of secreted CypB at endogenous levels unclear\",\n        \"Mechanism by which PPIase activity is required for CD147-ERK signaling not defined\",\n        \"No reciprocal validation across cell types\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CypB's isomerase activity mechanistically drives procollagen folding versus its scaffolding role in the hydroxylation complex, and whether its extracellular CD147 signaling occurs under normal physiology, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structure of the CypB/CRTAP/P3H1 complex\",\n        \"Substrate prolines isomerized during procollagen folding unmapped\",\n        \"Endogenous relevance of secreted CypB-CD147 axis untested in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"P3H1/CRTAP/CypB collagen prolyl 3-hydroxylation complex\"],\n    \"partners\": [\"CRTAP\", \"P3H1\", \"PDI\", \"P4H1\", \"CD147\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}