{"gene":"OCLN","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2010,"finding":"OCLN splice variants that retain the MARVEL domain are expressed on the cell membrane and are permissive for HCV entry, while variants lacking the MARVEL domain are expressed in the cytoplasm and are non-permissive for HCV infection. The MARVEL domain of OCLN is required for HCV interaction and cell-surface localization.","method":"Recombinant protein expression, in vitro HCV infectivity assays, cell membrane localization studies","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro infectivity assay with multiple isoforms tested, localization confirmed, functional consequence directly demonstrated","pmids":["20463075"],"is_preprint":false},{"year":2014,"finding":"miR-122 binds the 3' UTR of OCLN mRNA and downregulates OCLN protein expression, thereby reducing HCV entry into hepatocytes. Overexpression of miR-122 decreased OCLN protein by ~80% and reduced HCV entry by ~42%.","method":"Dual-luciferase 3' UTR reporter assay, lentiviral miR-122 overexpression, HCV pseudoparticle entry assay, immunofluorescence","journal":"Liver international","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — luciferase reporter confirms direct 3' UTR binding, functional consequence (reduced HCV entry) validated with orthogonal pseudoparticle assay","pmids":["25302477"],"is_preprint":false},{"year":2017,"finding":"miR-144 directly targets OCLN and ZO1, downregulating their expression and increasing intestinal epithelial permeability. Overexpression of OCLN and ZO1 eliminated the permeability-promoting effect of miR-144 in IBS-D rat colonic epithelial cells.","method":"Dual-luciferase reporter assay, miRNA mimic/inhibitor transfection, western blotting, rescue experiments with OCLN overexpression","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase confirms direct targeting, rescue experiments confirm OCLN is the functional target, single lab","pmids":["29258088"],"is_preprint":false},{"year":2020,"finding":"Lactobacillus casei LC01 enhances intestinal epithelial barrier function by downregulating miR-144 and upregulating OCLN and ZO1 expression. Overexpression of OCLN and ZO1 under LC01 treatment partially eliminated the permeability-promoting effect of miR-144.","method":"miRNA microarray, qRT-PCR, western blot, transfection of RNA oligoribonucleotides and pcDNA3.1 plasmid","journal":"Journal of microbiology and biotechnology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional rescue experiments confirm OCLN role downstream of miR-144, single lab, mechanistic pathway corroborated by prior work","pmids":["32807750"],"is_preprint":false},{"year":2021,"finding":"miR-122-5p directly targets OCLN, downregulating its expression in brain microvascular endothelial cells (BMECs). Overexpression of OCLN partially reversed miR-122-5p-induced increases in BMEC apoptosis and permeability.","method":"Dual-luciferase reporter assay, miRNA mimic transfection, OCLN overexpression rescue experiments, flow cytometry, western blot","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — dual-luciferase confirms direct targeting, rescue with OCLN overexpression confirms functional role, single lab","pmids":["34150006"],"is_preprint":false},{"year":2024,"finding":"S. pneumoniae extracellular vesicle cargo protein StkP (a eukaryotic-like serine-threonine kinase) phosphorylates BECN1 at Ser93 and Ser96, initiating autophagy that leads to autophagosomal degradation of OCLN and consequent alveolar epithelial barrier dysfunction. Deletion of stkP prevented OCLN degradation and protected mice from death.","method":"Proteomics of pEV cargo, co-immunoprecipitation, BECN1 phosphorylation assays, autophagy inhibition with BafA1/CQ, TEER measurements, stkP deletion mutant in vivo","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (proteomics, co-IP, phosphorylation assays, genetic deletion in vivo), mechanistic pathway from StkP → BECN1 phosphorylation → autophagy → OCLN degradation fully established","pmids":["38497494"],"is_preprint":false},{"year":2020,"finding":"CD81 and OCLN together are minimum essential factors required for HCV entry into non-hepatic tree shrew bone marrow-derived mesenchymal stem cells. Transduction of CD81/OCLN was sufficient to support HCV RNA replication and infectious virus production.","method":"Viral transduction of CD81/OCLN into BM-MSCs, HCV infection assay, RNA quantification","journal":"Journal of medical virology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional reconstitution in non-hepatic cells demonstrates necessary role of OCLN in HCV entry, single lab","pmids":["32056224"],"is_preprint":false},{"year":2025,"finding":"The OCLN carboxy-terminus forms a complex with the light intermediate chain (LIC) of dynein, linking tight junction cargo to the minus-end-directed motor protein. S471 phosphorylation is required for LIC binding, and S490 phosphorylation is required for trafficking. Expressing OCLN S490A mutant prevented endothelial cell proliferation and collateral angiogenesis. OCLN gene deletion targeting exon 5 (preventing full-length and isoform 4 expression) resulted in embryonic lethality.","method":"Co-immunoprecipitation, mutational analysis of phosphorylation sites (S471A, S490A), endothelial cell proliferation assays, in vivo collateral angiogenesis model, exon 5-targeted gene deletion","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mutagenesis of specific phosphorylation sites with functional readouts, in vivo deletion phenotype; preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"miR-20a overexpression suppresses DUSP3 expression and inhibits ubiquitination of OCLN in intestinal epithelial cells during sepsis, thereby preserving OCLN protein levels and alleviating intestinal barrier dysfunction.","method":"CLP mouse model, LPS-treated NCM460 cells, western blotting, RT-qPCR, immunofluorescence, OCLN knockdown/overexpression","journal":"In vitro cellular & developmental biology. Animal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic link between DUSP3 and OCLN ubiquitination is indirect; ubiquitination assay details not specified in abstract","pmids":["40392484"],"is_preprint":false}],"current_model":"OCLN (occludin) is an integral tight junction protein whose MARVEL domain is required for cell-surface localization and HCV entry; its carboxy-terminal tail acts as a dynein adaptor (binding the dynein light intermediate chain in a phosphorylation-dependent manner at S471/S490) to regulate tight junction cargo trafficking, vascular permeability, and collateral angiogenesis; OCLN protein levels are post-translationally regulated by autophagosomal degradation (triggered by bacterial StkP-mediated BECN1 phosphorylation) and by ubiquitination, and its mRNA is post-transcriptionally repressed by miR-144, miR-122, and miR-122-5p, which directly target its 3' UTR to reduce expression and increase epithelial/endothelial permeability."},"narrative":{"mechanistic_narrative":"OCLN (occludin) is an integral tight junction protein that controls epithelial and endothelial barrier integrity and also serves as an essential host entry factor for hepatitis C virus (HCV) [PMID:20463075, PMID:32056224]. Cell-surface localization and HCV permissiveness depend on the MARVEL domain: splice isoforms retaining it localize to the membrane and support viral interaction, whereas variants lacking it are cytoplasmic and non-permissive [PMID:20463075]. Together with CD81, OCLN constitutes a minimal set of factors sufficient to render even non-hepatic cells competent for HCV entry and replication [PMID:32056224]. Beyond its membrane role, the OCLN carboxy-terminus links tight junction cargo to the minus-end-directed motor by binding the dynein light intermediate chain (LIC) in a phosphorylation-dependent manner — S471 phosphorylation is required for LIC binding and S490 phosphorylation for trafficking — and this trafficking activity drives endothelial proliferation and collateral angiogenesis, with full-length OCLN loss being embryonic lethal. OCLN abundance is tightly regulated post-transcriptionally and post-translationally: its 3' UTR is directly targeted by miR-122, miR-144, and miR-122-5p to lower protein levels and increase barrier permeability across hepatic, intestinal, and brain microvascular contexts [PMID:25302477, PMID:29258088, PMID:34150006], and its protein stability is controlled by autophagosomal degradation and ubiquitination [PMID:38497494, PMID:40392484]. Pathogen-driven OCLN loss is a route to barrier failure, as S. pneumoniae StkP phosphorylates BECN1 to trigger autophagy-dependent OCLN degradation and alveolar barrier dysfunction [PMID:38497494].","teleology":[{"year":2010,"claim":"Established that OCLN's MARVEL domain dictates both its cell-surface localization and its function as an HCV entry factor, defining the structural determinant of viral permissiveness.","evidence":"Recombinant isoform expression with localization studies and in vitro HCV infectivity assays","pmids":["20463075"],"confidence":"High","gaps":["Does not define the molecular interface between the MARVEL domain and HCV","Does not address OCLN's tight-junction barrier function"]},{"year":2014,"claim":"Showed that OCLN levels are set post-transcriptionally via direct 3' UTR targeting by miR-122, coupling host miRNA control to HCV entry efficiency.","evidence":"Dual-luciferase 3' UTR reporter, miR-122 overexpression, and HCV pseudoparticle entry assay in hepatocytes","pmids":["25302477"],"confidence":"High","gaps":["Does not establish the upstream regulators of miR-122 in this context","Effect on barrier permeability not measured"]},{"year":2017,"claim":"Extended miRNA control of OCLN to barrier permeability, demonstrating miR-144 directly represses OCLN (and ZO1) to increase intestinal epithelial permeability.","evidence":"Dual-luciferase reporter, miRNA mimic/inhibitor transfection, and OCLN overexpression rescue in IBS-D rat colonic epithelium","pmids":["29258088"],"confidence":"Medium","gaps":["Single-lab finding","Relative contribution of OCLN versus ZO1 to the permeability phenotype not resolved"]},{"year":2020,"claim":"Placed OCLN downstream of a probiotic-modulated miR-144 axis and confirmed CD81/OCLN as a minimal sufficient module for HCV entry in non-hepatic cells.","evidence":"miRNA microarray with OCLN rescue (L. casei study) and CD81/OCLN transduction of tree shrew BM-MSCs with HCV infection assay","pmids":["32807750","32056224"],"confidence":"Medium","gaps":["CD81/OCLN cooperation mechanism at the membrane not defined","Probiotic regulation of miR-144 mechanism not established"]},{"year":2021,"claim":"Generalized OCLN's miRNA regulation to the neurovascular unit, showing miR-122-5p directly targets OCLN to increase brain microvascular endothelial apoptosis and permeability.","evidence":"Dual-luciferase reporter, miRNA mimic transfection, and OCLN overexpression rescue with flow cytometry in BMECs","pmids":["34150006"],"confidence":"Medium","gaps":["Single-lab finding","Link between OCLN loss and apoptosis mechanism not defined"]},{"year":2024,"claim":"Defined a pathogen-driven post-translational route to OCLN loss, in which bacterial StkP phosphorylates BECN1 to trigger autophagosomal OCLN degradation and barrier failure.","evidence":"pEV proteomics, co-IP, BECN1 phosphorylation assays, autophagy inhibition, TEER, and stkP deletion in vivo","pmids":["38497494"],"confidence":"High","gaps":["Mechanism targeting OCLN specifically to autophagosomes not defined","Whether host autophagy regulators reproduce this in the absence of bacteria unaddressed"]},{"year":2025,"claim":"Revealed a previously uncharacterized motor-adaptor function: the OCLN C-terminus binds dynein LIC in a phosphorylation-dependent manner to traffic tight junction cargo and drive endothelial proliferation and collateral angiogenesis.","evidence":"Reciprocal co-IP, S471A/S490A mutagenesis with functional readouts, in vivo collateral angiogenesis, and exon 5-targeted deletion (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Kinase(s) phosphorylating S471/S490 not identified","Cargo identity transported by the OCLN-dynein complex not defined"]},{"year":2025,"claim":"Implicated ubiquitination as an additional OCLN stability control point, with a miR-20a/DUSP3 axis modulating OCLN ubiquitination during sepsis-associated barrier dysfunction.","evidence":"CLP mouse model and LPS-treated NCM460 cells with OCLN knockdown/overexpression, western blot, and immunofluorescence","pmids":["40392484"],"confidence":"Low","gaps":["DUSP3-to-OCLN ubiquitination link is indirect and ubiquitination assay details unspecified","Responsible E3 ligase not identified","Single-lab finding"]},{"year":null,"claim":"How OCLN integrates its membrane barrier role, viral receptor function, and dynein-dependent cargo trafficking into a single regulated program remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the OCLN-dynein LIC complex","Identity of kinases and E3 ligases controlling OCLN trafficking and turnover unknown","Causal Mendelian disease link not established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,6]}],"complexes":["tight junction"],"partners":["CD81","DYNEIN LIC (DYNC1LI1)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16625","full_name":"Occludin","aliases":[],"length_aa":522,"mass_kda":59.1,"function":"May play a role in the formation and regulation of the tight junction (TJ) paracellular permeability barrier. It is able to induce adhesion when expressed in cells lacking tight junctions (Microbial infection) Acts as a coreceptor for hepatitis C virus (HCV) in hepatocytes","subcellular_location":"Cell membrane; Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/Q16625/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OCLN","classification":"Not Classified","n_dependent_lines":31,"n_total_lines":1208,"dependency_fraction":0.02566225165562914},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OCLN","total_profiled":1310},"omim":[{"mim_id":"621451","title":"SMALL NUCLEOLAR RNA HOST GENE 12; SNHG12","url":"https://www.omim.org/entry/621451"},{"mim_id":"621447","title":"ZINC FINGER PROTEIN 787; ZNF787","url":"https://www.omim.org/entry/621447"},{"mim_id":"617579","title":"CLAUDIN 10; CLDN10","url":"https://www.omim.org/entry/617579"},{"mim_id":"617005","title":"CLAUDIN 17; CLDN17","url":"https://www.omim.org/entry/617005"},{"mim_id":"616432","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 18; ARHGEF18","url":"https://www.omim.org/entry/616432"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"thyroid gland","ntpm":29.4}],"url":"https://www.proteinatlas.org/search/OCLN"},"hgnc":{"alias_symbol":["PPP1R115"],"prev_symbol":[]},"alphafold":{"accession":"Q16625","domains":[{"cath_id":"-","chopping":"54-91_133-199_240-281","consensus_level":"high","plddt":82.4771,"start":54,"end":281},{"cath_id":"1.10.287","chopping":"414-520","consensus_level":"high","plddt":91.3524,"start":414,"end":520}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16625","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16625-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16625-F1-predicted_aligned_error_v6.png","plddt_mean":65.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OCLN","jax_strain_url":"https://www.jax.org/strain/search?query=OCLN"},"sequence":{"accession":"Q16625","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16625.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16625/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16625"}},"corpus_meta":[{"pmid":"29258088","id":"PMC_29258088","title":"MiR-144 Increases Intestinal Permeability in IBS-D Rats by Targeting OCLN and ZO1.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29258088","citation_count":67,"is_preprint":false},{"pmid":"38497494","id":"PMC_38497494","title":"Streptococcus pneumoniae extracellular vesicles aggravate alveolar epithelial barrier disruption via autophagic degradation of OCLN (occludin).","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/38497494","citation_count":34,"is_preprint":false},{"pmid":"32807750","id":"PMC_32807750","title":"Lactobacillus casei LC01 Regulates Intestinal Epithelial Permeability through miR-144 Targeting of OCLN and ZO1.","date":"2020","source":"Journal of microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32807750","citation_count":33,"is_preprint":false},{"pmid":"20463075","id":"PMC_20463075","title":"Splicing diversity of the human OCLN gene and its biological significance for hepatitis C virus entry.","date":"2010","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/20463075","citation_count":30,"is_preprint":false},{"pmid":"34150006","id":"PMC_34150006","title":"Exosomes containing miR-122-5p secreted by LPS-induced neutrophils regulate the apoptosis and permeability of brain microvascular endothelial cells by targeting OCLN.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34150006","citation_count":22,"is_preprint":false},{"pmid":"28179633","id":"PMC_28179633","title":"Band-like calcification with simplified gyration and polymicrogyria: report of 10 new families and identification of five novel OCLN mutations.","date":"2017","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28179633","citation_count":21,"is_preprint":false},{"pmid":"25302477","id":"PMC_25302477","title":"MiR-122 decreases HCV entry into hepatocytes through binding to the 3' UTR of OCLN mRNA.","date":"2014","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/25302477","citation_count":18,"is_preprint":false},{"pmid":"28490769","id":"PMC_28490769","title":"Increased cerebral expressions of MMPs, CLDN5, OCLN, ZO1 and AQPs are associated with brain edema following fatal heat stroke.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28490769","citation_count":16,"is_preprint":false},{"pmid":"28184927","id":"PMC_28184927","title":"Downregulation of OCLN and GAS1 in clear cell renal cell carcinoma.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28184927","citation_count":11,"is_preprint":false},{"pmid":"28386946","id":"PMC_28386946","title":"Comprehensive molecular screening strategy of OCLN in band-like calcification with simplified gyration and polymicrogyria.","date":"2017","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28386946","citation_count":9,"is_preprint":false},{"pmid":"32240828","id":"PMC_32240828","title":"A homozygote frameshift mutation in OCLN gene result in Pseudo-TORCH syndrome type I: A case report extending the phenotype with central diabetes insipidus and renal dysfunction.","date":"2020","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32240828","citation_count":9,"is_preprint":false},{"pmid":"32056224","id":"PMC_32056224","title":"Tree shrew bone marrow-derived mesenchymal stem cells express CD81, OCLN, and miR-122, facilitating the entire hepatitis C virus life cycle.","date":"2020","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/32056224","citation_count":8,"is_preprint":false},{"pmid":"30814850","id":"PMC_30814850","title":"Effect of calprotectin subunit S100A9 on the expression and methylation of OCLN in human melanoma cell line A-375.","date":"2017","source":"Turkish journal of biology = Turk biyoloji dergisi","url":"https://pubmed.ncbi.nlm.nih.gov/30814850","citation_count":6,"is_preprint":false},{"pmid":"34704946","id":"PMC_34704946","title":"OCLN gene variants identified in three patients with severe neurodevelopmental disorder associated with epilepsy, intellectual disability and malformation of cortical development.","date":"2021","source":"Epileptic disorders : international epilepsy journal with videotape","url":"https://pubmed.ncbi.nlm.nih.gov/34704946","citation_count":4,"is_preprint":false},{"pmid":"35834877","id":"PMC_35834877","title":"LncRNA ALDB-898 modulates intestinal epithelial cell damage caused by Clostridium perfringens type C in piglet by regulating ssc-miR-122-5p/OCLN signaling.","date":"2022","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35834877","citation_count":3,"is_preprint":false},{"pmid":"28053600","id":"PMC_28053600","title":"Alginate-embedded HuH-7 cells increase MMP-9 and reduce OCLN expression in vitro.","date":"2017","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/28053600","citation_count":3,"is_preprint":false},{"pmid":"34573918","id":"PMC_34573918","title":"A Fetus with Congenital Microcephaly, Microphthalmia and Cataract Was Detected with Biallelic Variants in the OCLN Gene: A Case Report.","date":"2021","source":"Diagnostics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34573918","citation_count":2,"is_preprint":false},{"pmid":"34515239","id":"PMC_34515239","title":"MiR-224-5p Targeting OCLN Promotes the Proliferation, Migration, and Invasion of Clear Cell Renal Cell Carcinoma Cells.","date":"2021","source":"Urologia internationalis","url":"https://pubmed.ncbi.nlm.nih.gov/34515239","citation_count":1,"is_preprint":false},{"pmid":"41594443","id":"PMC_41594443","title":"Testicular Gap (CX43) and Tight Junction (OCLN, CLDN3, 5 and 11) Components in the Dog Are Affected by GnRH-Mediated Downregulation.","date":"2026","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/41594443","citation_count":0,"is_preprint":false},{"pmid":"40392484","id":"PMC_40392484","title":"Overexpression of miR-20a targeting DUSP3 inhibits OCLN ubiquitination levels and alleviates sepsis induced intestinal barrier dysfunction.","date":"2025","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/40392484","citation_count":0,"is_preprint":false},{"pmid":"42128054","id":"PMC_42128054","title":"Fibro-tubular tumors of the thyroid: an emerging thyroid neoplasm characterized by distinctive morphology and recurrent OCLN::PRKCI gene fusions spanning the adenoma-carcinoma spectrum.","date":"2026","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/42128054","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.17.688818","title":"Vascular Basement Membrane Laminins Modulate Functional Zonation of Cerebral Microvessels","date":"2025-11-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.17.688818","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.12.659326","title":"Occludin Acts as a Dynein Adaptor Regulating Permeability and Collateral Angiogenesis","date":"2025-06-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.12.659326","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.18.677083","title":"Nutritional vitamin E or plant extracts affect the immune response and mammary epithelium integrity during intramammary lipopolysaccharide challenge in early lactation","date":"2025-09-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.18.677083","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.21.683634","title":"Human cortico-vascular assembloids reveal a CELF2-AHNAK-dependent switch from neuronal to endothelial tropism in glioblastoma cells","date":"2025-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.21.683634","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.16.649253","title":"Shift in gut microbiota composition and mitigation of diet-induced atherogenesis in mice after prolonged consumption of a traditionally fermented soybean","date":"2025-04-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.16.649253","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.24.639874","title":"<i>NOR1</i>  and Mitophagy: An Insight into Sertoli Cell Function Regulating Spermatogenesis","date":"2025-02-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.24.639874","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.05.636626","title":"Sex-dependent effects of intestinal epithelial TLR4 deletion induced before activity-based anorexia","date":"2025-02-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.05.636626","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19750,"output_tokens":2349,"usd":0.047242,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9439,"output_tokens":3049,"usd":0.06171,"stage2_stop_reason":"end_turn"},"total_usd":0.108952,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"OCLN splice variants that retain the MARVEL domain are expressed on the cell membrane and are permissive for HCV entry, while variants lacking the MARVEL domain are expressed in the cytoplasm and are non-permissive for HCV infection. The MARVEL domain of OCLN is required for HCV interaction and cell-surface localization.\",\n      \"method\": \"Recombinant protein expression, in vitro HCV infectivity assays, cell membrane localization studies\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro infectivity assay with multiple isoforms tested, localization confirmed, functional consequence directly demonstrated\",\n      \"pmids\": [\"20463075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-122 binds the 3' UTR of OCLN mRNA and downregulates OCLN protein expression, thereby reducing HCV entry into hepatocytes. Overexpression of miR-122 decreased OCLN protein by ~80% and reduced HCV entry by ~42%.\",\n      \"method\": \"Dual-luciferase 3' UTR reporter assay, lentiviral miR-122 overexpression, HCV pseudoparticle entry assay, immunofluorescence\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — luciferase reporter confirms direct 3' UTR binding, functional consequence (reduced HCV entry) validated with orthogonal pseudoparticle assay\",\n      \"pmids\": [\"25302477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-144 directly targets OCLN and ZO1, downregulating their expression and increasing intestinal epithelial permeability. Overexpression of OCLN and ZO1 eliminated the permeability-promoting effect of miR-144 in IBS-D rat colonic epithelial cells.\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA mimic/inhibitor transfection, western blotting, rescue experiments with OCLN overexpression\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase confirms direct targeting, rescue experiments confirm OCLN is the functional target, single lab\",\n      \"pmids\": [\"29258088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Lactobacillus casei LC01 enhances intestinal epithelial barrier function by downregulating miR-144 and upregulating OCLN and ZO1 expression. Overexpression of OCLN and ZO1 under LC01 treatment partially eliminated the permeability-promoting effect of miR-144.\",\n      \"method\": \"miRNA microarray, qRT-PCR, western blot, transfection of RNA oligoribonucleotides and pcDNA3.1 plasmid\",\n      \"journal\": \"Journal of microbiology and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional rescue experiments confirm OCLN role downstream of miR-144, single lab, mechanistic pathway corroborated by prior work\",\n      \"pmids\": [\"32807750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-122-5p directly targets OCLN, downregulating its expression in brain microvascular endothelial cells (BMECs). Overexpression of OCLN partially reversed miR-122-5p-induced increases in BMEC apoptosis and permeability.\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA mimic transfection, OCLN overexpression rescue experiments, flow cytometry, western blot\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — dual-luciferase confirms direct targeting, rescue with OCLN overexpression confirms functional role, single lab\",\n      \"pmids\": [\"34150006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"S. pneumoniae extracellular vesicle cargo protein StkP (a eukaryotic-like serine-threonine kinase) phosphorylates BECN1 at Ser93 and Ser96, initiating autophagy that leads to autophagosomal degradation of OCLN and consequent alveolar epithelial barrier dysfunction. Deletion of stkP prevented OCLN degradation and protected mice from death.\",\n      \"method\": \"Proteomics of pEV cargo, co-immunoprecipitation, BECN1 phosphorylation assays, autophagy inhibition with BafA1/CQ, TEER measurements, stkP deletion mutant in vivo\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (proteomics, co-IP, phosphorylation assays, genetic deletion in vivo), mechanistic pathway from StkP → BECN1 phosphorylation → autophagy → OCLN degradation fully established\",\n      \"pmids\": [\"38497494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD81 and OCLN together are minimum essential factors required for HCV entry into non-hepatic tree shrew bone marrow-derived mesenchymal stem cells. Transduction of CD81/OCLN was sufficient to support HCV RNA replication and infectious virus production.\",\n      \"method\": \"Viral transduction of CD81/OCLN into BM-MSCs, HCV infection assay, RNA quantification\",\n      \"journal\": \"Journal of medical virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional reconstitution in non-hepatic cells demonstrates necessary role of OCLN in HCV entry, single lab\",\n      \"pmids\": [\"32056224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The OCLN carboxy-terminus forms a complex with the light intermediate chain (LIC) of dynein, linking tight junction cargo to the minus-end-directed motor protein. S471 phosphorylation is required for LIC binding, and S490 phosphorylation is required for trafficking. Expressing OCLN S490A mutant prevented endothelial cell proliferation and collateral angiogenesis. OCLN gene deletion targeting exon 5 (preventing full-length and isoform 4 expression) resulted in embryonic lethality.\",\n      \"method\": \"Co-immunoprecipitation, mutational analysis of phosphorylation sites (S471A, S490A), endothelial cell proliferation assays, in vivo collateral angiogenesis model, exon 5-targeted gene deletion\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mutagenesis of specific phosphorylation sites with functional readouts, in vivo deletion phenotype; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-20a overexpression suppresses DUSP3 expression and inhibits ubiquitination of OCLN in intestinal epithelial cells during sepsis, thereby preserving OCLN protein levels and alleviating intestinal barrier dysfunction.\",\n      \"method\": \"CLP mouse model, LPS-treated NCM460 cells, western blotting, RT-qPCR, immunofluorescence, OCLN knockdown/overexpression\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic link between DUSP3 and OCLN ubiquitination is indirect; ubiquitination assay details not specified in abstract\",\n      \"pmids\": [\"40392484\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OCLN (occludin) is an integral tight junction protein whose MARVEL domain is required for cell-surface localization and HCV entry; its carboxy-terminal tail acts as a dynein adaptor (binding the dynein light intermediate chain in a phosphorylation-dependent manner at S471/S490) to regulate tight junction cargo trafficking, vascular permeability, and collateral angiogenesis; OCLN protein levels are post-translationally regulated by autophagosomal degradation (triggered by bacterial StkP-mediated BECN1 phosphorylation) and by ubiquitination, and its mRNA is post-transcriptionally repressed by miR-144, miR-122, and miR-122-5p, which directly target its 3' UTR to reduce expression and increase epithelial/endothelial permeability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OCLN (occludin) is an integral tight junction protein that controls epithelial and endothelial barrier integrity and also serves as an essential host entry factor for hepatitis C virus (HCV) [#0, #6]. Cell-surface localization and HCV permissiveness depend on the MARVEL domain: splice isoforms retaining it localize to the membrane and support viral interaction, whereas variants lacking it are cytoplasmic and non-permissive [#0]. Together with CD81, OCLN constitutes a minimal set of factors sufficient to render even non-hepatic cells competent for HCV entry and replication [#6]. Beyond its membrane role, the OCLN carboxy-terminus links tight junction cargo to the minus-end-directed motor by binding the dynein light intermediate chain (LIC) in a phosphorylation-dependent manner — S471 phosphorylation is required for LIC binding and S490 phosphorylation for trafficking — and this trafficking activity drives endothelial proliferation and collateral angiogenesis, with full-length OCLN loss being embryonic lethal [#7]. OCLN abundance is tightly regulated post-transcriptionally and post-translationally: its 3' UTR is directly targeted by miR-122, miR-144, and miR-122-5p to lower protein levels and increase barrier permeability across hepatic, intestinal, and brain microvascular contexts [#1, #2, #4], and its protein stability is controlled by autophagosomal degradation and ubiquitination [#5, #8]. Pathogen-driven OCLN loss is a route to barrier failure, as S. pneumoniae StkP phosphorylates BECN1 to trigger autophagy-dependent OCLN degradation and alveolar barrier dysfunction [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that OCLN's MARVEL domain dictates both its cell-surface localization and its function as an HCV entry factor, defining the structural determinant of viral permissiveness.\",\n      \"evidence\": \"Recombinant isoform expression with localization studies and in vitro HCV infectivity assays\",\n      \"pmids\": [\"20463075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the molecular interface between the MARVEL domain and HCV\", \"Does not address OCLN's tight-junction barrier function\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed that OCLN levels are set post-transcriptionally via direct 3' UTR targeting by miR-122, coupling host miRNA control to HCV entry efficiency.\",\n      \"evidence\": \"Dual-luciferase 3' UTR reporter, miR-122 overexpression, and HCV pseudoparticle entry assay in hepatocytes\",\n      \"pmids\": [\"25302477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not establish the upstream regulators of miR-122 in this context\", \"Effect on barrier permeability not measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended miRNA control of OCLN to barrier permeability, demonstrating miR-144 directly represses OCLN (and ZO1) to increase intestinal epithelial permeability.\",\n      \"evidence\": \"Dual-luciferase reporter, miRNA mimic/inhibitor transfection, and OCLN overexpression rescue in IBS-D rat colonic epithelium\",\n      \"pmids\": [\"29258088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Relative contribution of OCLN versus ZO1 to the permeability phenotype not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed OCLN downstream of a probiotic-modulated miR-144 axis and confirmed CD81/OCLN as a minimal sufficient module for HCV entry in non-hepatic cells.\",\n      \"evidence\": \"miRNA microarray with OCLN rescue (L. casei study) and CD81/OCLN transduction of tree shrew BM-MSCs with HCV infection assay\",\n      \"pmids\": [\"32807750\", \"32056224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CD81/OCLN cooperation mechanism at the membrane not defined\", \"Probiotic regulation of miR-144 mechanism not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalized OCLN's miRNA regulation to the neurovascular unit, showing miR-122-5p directly targets OCLN to increase brain microvascular endothelial apoptosis and permeability.\",\n      \"evidence\": \"Dual-luciferase reporter, miRNA mimic transfection, and OCLN overexpression rescue with flow cytometry in BMECs\",\n      \"pmids\": [\"34150006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Link between OCLN loss and apoptosis mechanism not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a pathogen-driven post-translational route to OCLN loss, in which bacterial StkP phosphorylates BECN1 to trigger autophagosomal OCLN degradation and barrier failure.\",\n      \"evidence\": \"pEV proteomics, co-IP, BECN1 phosphorylation assays, autophagy inhibition, TEER, and stkP deletion in vivo\",\n      \"pmids\": [\"38497494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism targeting OCLN specifically to autophagosomes not defined\", \"Whether host autophagy regulators reproduce this in the absence of bacteria unaddressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a previously uncharacterized motor-adaptor function: the OCLN C-terminus binds dynein LIC in a phosphorylation-dependent manner to traffic tight junction cargo and drive endothelial proliferation and collateral angiogenesis.\",\n      \"evidence\": \"Reciprocal co-IP, S471A/S490A mutagenesis with functional readouts, in vivo collateral angiogenesis, and exon 5-targeted deletion (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Kinase(s) phosphorylating S471/S490 not identified\", \"Cargo identity transported by the OCLN-dynein complex not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated ubiquitination as an additional OCLN stability control point, with a miR-20a/DUSP3 axis modulating OCLN ubiquitination during sepsis-associated barrier dysfunction.\",\n      \"evidence\": \"CLP mouse model and LPS-treated NCM460 cells with OCLN knockdown/overexpression, western blot, and immunofluorescence\",\n      \"pmids\": [\"40392484\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"DUSP3-to-OCLN ubiquitination link is indirect and ubiquitination assay details unspecified\", \"Responsible E3 ligase not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OCLN integrates its membrane barrier role, viral receptor function, and dynein-dependent cargo trafficking into a single regulated program remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the OCLN-dynein LIC complex\", \"Identity of kinases and E3 ligases controlling OCLN trafficking and turnover unknown\", \"Causal Mendelian disease link not established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [\"tight junction\"],\n    \"partners\": [\"CD81\", \"dynein LIC (DYNC1LI1)\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}