{"gene":"OCIAD1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2003,"finding":"Asrij/OCIAD1 encodes a novel conserved predicted transmembrane protein of 247 amino acids that localizes to lysosomes and endosomes, as determined by subcellular fractionation and localization studies in mouse embryonic stem cells and during development.","method":"Subcellular localization (lysosomes/endosomes) by direct imaging/fractionation; expression analysis in ES cells and embryos","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment, replicated in multiple tissue contexts in a single study, but no functional mutagenesis","pmids":["12889067"],"is_preprint":false},{"year":2011,"finding":"Drosophila Asrij localizes to a subset of endocytic vesicles and is required for proper Notch trafficking; loss of asrij causes accumulation of Notch in sorting endosomes and increased crystal cell differentiation, indicating Asrij regulates Notch signaling through endosomal trafficking.","method":"Genetic loss-of-function (asrij null mutants), immunostaining of endosomal markers, in vitro fluorescent probe trafficking assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, imaging, in vitro trafficking assay), replicated in multiple contexts within the study","pmids":["22110713"],"is_preprint":false},{"year":2013,"finding":"Asrij/OCIAD1 is an endosomal protein that dose-dependently modulates JAK/STAT signaling to maintain stem cell pluripotency; STAT3 colocalizes with Asrij in endosomes and interacts with it biochemically, suggesting Asrij provides an endosomal scaffold for STAT3 activation.","method":"Co-immunoprecipitation (biochemical interaction), colocalization imaging (endosomal compartment), genetic gain/loss-of-function in mouse ESCs and Drosophila HSCs, cross-species rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical interaction, colocalization, genetic epistasis across two species with rescue experiment","pmids":["23972987"],"is_preprint":false},{"year":2014,"finding":"Activated ARF1 (ARF1-GTP) physically interacts with Asrij and regulates its levels in blood cells; perturbation of ARF1 activation leads to aberrant Notch trafficking with Notch intracellular domain stalled in sorting endosomes, placing ARF1 upstream of Asrij in endocytic control of hematopoiesis.","method":"Genetic epistasis (ARF1 knockdown, GEF/GAP manipulation), co-immunoprecipitation/interaction assay, Notch trafficking analysis by immunostaining","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple alleles, interaction assay, trafficking readout, multiple orthogonal methods in one study","pmids":["24707047"],"is_preprint":false},{"year":2008,"finding":"OCIAD1 overexpression in ovarian cancer cells increases LPA-induced cell adhesion to collagen I and laminin 10/11, and this effect is not blocked by PKC or PI3K inhibitors, indicating OCIAD1 promotes cell adhesion through a PKC/PI3K-independent mechanism.","method":"Overexpression and knockdown in HEY ovarian cancer cells, cell adhesion assay with pharmacological inhibitors (LY294002, GF109203X)","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain- and loss-of-function with defined cellular phenotype and pathway exclusion, single lab","pmids":["18328549"],"is_preprint":false},{"year":2010,"finding":"LPA induces OCIAD1 serine phosphorylation within 2 hours and upregulates OCIAD1 expression via the MKK6/p38 MAPK pathway; OCIAD1 knockdown inhibits LPA-induced adhesion to collagen I and laminin 10/11 and specifically to alpha2, alpha5, alphaV, and beta1 integrins; proteomic studies show OCIAD1 is physically associated with alpha-actin 4 and beta-actin, indicating a role in cytoskeletal regulation.","method":"LPA stimulation assay, serine phosphorylation detection, p38 inhibitor (pharmacological), MKK6 transfection, knockdown, integrin-specific adhesion assay, co-immunoprecipitation/proteomics (OCIAD1–actin interaction)","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (phosphorylation, pharmacology, knockdown, proteomics), single lab","pmids":["20515946"],"is_preprint":false},{"year":2017,"finding":"The ARF1-Asrij endosomal axis regulates the cellular immune response by controlling crystal cell melanization and phenoloxidase activity, and suppresses Toll pathway anti-microbial peptides by regulating ubiquitination of the Toll inhibitor Cactus; Asrij (but not ARF1) is required for Imd pathway AMP production.","method":"Genetic loss-of-function (ARF1 and asrij mutants), AMP and phenoloxidase activity assays, ubiquitination analysis, infection survival assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple pathway readouts, single lab","pmids":["28273919"],"is_preprint":false},{"year":2018,"finding":"OCIAD1 interacts with mitochondrial Complex I and regulates its activity; OCIAD1 depletion in human pluripotent stem cells increases oxidative phosphorylation (OXPHOS), and pharmacological inhibition of Complex I rescues the differentiation defects caused by OCIAD1 loss, placing OCIAD1 as a regulator of mitochondrial Complex I activity to maintain pluripotency.","method":"Co-immunoprecipitation (OCIAD1-Complex I interaction), energy metabolic assays (live cell OXPHOS), CRISPR/Cas9 knockout, pharmacological rescue (Complex I inhibitor)","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical interaction, functional metabolic assay, genetic KO, and pharmacological epistasis in one study","pmids":["29937147"],"is_preprint":false},{"year":2019,"finding":"Asrij/OCIAD1 sequesters CSN5 (COP9 signalosome subunit 5) via its conserved OCIA domain, preventing CSN5-mediated p53 ubiquitination and degradation; loss of Asrij in mouse HSCs leads to increased polyubiquitinated proteins and p53 degradation, and Nutlin-3 treatment (p53 stabilization) restores normal HSPC frequencies in asrij knockout mice.","method":"Co-immunoprecipitation (Asrij-CSN5 interaction via OCIA domain), ubiquitination assay, asrij knockout mouse model, pharmacological rescue (Nutlin-3), transplantation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific interaction, in vivo KO phenotype, pharmacological rescue and molecular mechanism in a single rigorous study","pmids":["30952670"],"is_preprint":false},{"year":2019,"finding":"OCIAD1 regulates ATM expression/function in pancreatic ductal adenocarcinoma cells to promote cell migration; OCIAD1 downregulation inhibits migration and is associated with increased ATM.","method":"Knockdown/overexpression in PDAC cell lines, migration assay, gene chip correlation analysis","journal":"Pancreatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single functional assay, limited mechanistic resolution","pmids":["31221523"],"is_preprint":false},{"year":2020,"finding":"HCV NS3-4A protease cleaves OCIAD1 at Cys38, near a predicted transmembrane segment; cleavage occurs in heterologous systems, HCV replicons, cell-culture HCV, and human liver biopsies from chronic HCV patients; domain-swapping experiments show that the sequence surrounding Cys38 and the transmembrane segment determine substrate selectivity for NS3-4A.","method":"Quantitative proteomics (SILAC-MS), heterologous expression cleavage assay, replicon system, cell culture HCV system, patient liver biopsies, domain-swapping mutagenesis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — cleavage site identified by mutagenesis and domain swapping, validated in multiple independent systems including patient material","pmids":["32697788"],"is_preprint":false},{"year":2020,"finding":"Elevated OCIAD1 interacts with BCL-2 to impair mitochondrial function in neurons; OCIAD1 levels are increased by Aβ/GSK-3β signaling, and elevated OCIAD1 increases neuronal susceptibility to AD pathological challenges.","method":"Co-immunoprecipitation (OCIAD1-BCL-2 interaction), mitochondrial function assays, overexpression in neuronal cells, bioinformatics-guided candidate identification","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — biochemical interaction and functional assay, single lab, multiple methods but limited genetic validation","pmids":["31931285"],"is_preprint":false},{"year":2021,"finding":"OCIAD1 is an inner mitochondrial membrane protein that forms a complex with supramolecular prohibitin assemblies and is required for normal steady-state levels of mitochondrial Complex III and for proteolytic processing of the catalytic subunit cytochrome c (CYC1) by the IMMP2L protease; in OCIAD1-depleted mitochondria, unprocessed CYC1 is hemylated and incorporated into Complex III.","method":"Genome-wide CRISPRi screen, CRISPRi depletion, mitochondrial fractionation, co-immunoprecipitation (OCIAD1-prohibitin complex), Complex III assembly assay, CYC1 processing assay, proteomics","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — genome-wide functional screen, biochemical reconstitution of complex, multiple orthogonal methods including fractionation, interaction, and substrate processing assays in one study","pmids":["34034859"],"is_preprint":false},{"year":2021,"finding":"Asrij/OCIAD1 localizes to mitochondria of larval blood cells and its depletion causes elongated mitochondria and reduced mitochondrial dynamics; genetic interaction studies show Asrij synergizes with fission regulator Drp1 and fusion regulator Marf/Mitofusin to control crystal cell differentiation and Notch signaling in Drosophila progenitors.","method":"Live imaging of mitochondrial dynamics (knockdown hemocytes and OCIAD1 KO hESCs), genetic epistasis (Drp1 and Marf knockdown with asrij depletion), Notch signaling readout","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with functional consequence, genetic epistasis in two model systems, single lab","pmids":["34295888"],"is_preprint":false},{"year":2021,"finding":"Asrij/OCIAD1 physically interacts with ARF1 as confirmed by a protein complementation assay using bacterially expressed purified proteins; sophorolipids improve solubility and monodispersibility of purified Asrij membrane protein.","method":"Protein complementation assay (in vitro with purified recombinant proteins), heterologous expression and purification, crystallization trials","journal":"The Journal of membrane biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted physical interaction with purified components, but single lab and limited functional follow-up in this study","pmids":["33433647"],"is_preprint":false},{"year":2022,"finding":"In asrij knockout mouse HSCs, organelle dysfunction occurs: damaged mitochondria with elevated ROS, impaired endosomal trafficking (increased cleaved Notch1, reduced Rab5), and reduced 26S proteasome activity; pharmacological correction of mitochondrial and proteasome activity restores HSC and myeloid cell frequencies, and LPA-induced Asrij upregulation in aged mice rescues these organelle functions.","method":"asrij knockout mouse, mitochondrial function assay, ROS measurement, endosomal trafficking markers (Notch1, Rab5), proteasome activity assay, pharmacological rescue, LPA stimulation in aged mice","journal":"Aging cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple organelle functional readouts, pharmacological epistasis, and in vivo rescue, multiple orthogonal methods","pmids":["35289070"],"is_preprint":false},{"year":2024,"finding":"OCIAD1 assembles with the prohibitin complex to protect the TIMM17A variant of the mitochondrial TIM23 translocase from degradation by the YME1L protease; prohibitins are required to stabilize both TIMM17A- and TIMM17B-containing TIM23 variants; OCIAD1 expression is in turn regulated by TIM23 complex status.","method":"Co-immunoprecipitation (OCIAD1-prohibitin-TIM23 complex), genetic depletion of OCIAD1 and prohibitins, protease (YME1L) activity assay, TIM23 stability assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal complex interaction, identification of specific protease (YME1L) and substrate variant (TIMM17A), multiple orthogonal methods in a single rigorous study","pmids":["39630581"],"is_preprint":false},{"year":2025,"finding":"OCIAD1 knockout cells show extensive lipidome rearrangement including decreased ether phospholipids and phospholipids with odd numbers of carbons, associated with global loss of peroxisomal proteins and aberrant peroxisomal morphology, and increased mitochondrial fatty acid β-oxidation proteins; OCIAD1 is proposed to act at the mitochondria-peroxisome interface to balance lipid metabolism, with direct impact on FAR1 and ABCD3 enzymes.","method":"Mass spectrometry-based lipidomics and proteomics (mitochondrial fraction and whole cell) of OCIAD1 KO cells, proximity labeling meta-analysis, peroxisome morphology imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative multi-omic approach (proteomics + lipidomics) with morphological validation, single lab, no direct enzymatic reconstitution","pmids":["40211913"],"is_preprint":false},{"year":2025,"finding":"Asrij depletion in APP/PS1 AD mice reduces STAT3 and NF-κB activation in microglia, increases mitochondrial activity, and impedes acquisition of the pro-inflammatory disease-associated microglia (DAM) state; loss of Asrij reduces proinflammatory cytokine levels and Aβ plaque load, positioning Asrij as a promoter of neuroinflammatory DAM signaling.","method":"asrij knockout in APP/PS1 mice, flow cytometry, RNA sequencing of AD microglia, confocal microscopy, immunohistochemistry, STAT3/NF-κB activation assay, mitochondrial activity assay, behavioral testing","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO with transcriptomic and biochemical pathway readouts, single lab, multiple methods","pmids":["40114191"],"is_preprint":false}],"current_model":"OCIAD1/Asrij is a conserved inner mitochondrial membrane (and endosomal) scaffold protein that: (1) assembles with prohibitin complexes to stabilize Complex III assembly by chaperoning CYC1 processing via IMMP2L, and to protect the TIMM17A variant of the TIM23 translocase from YME1L-mediated degradation; (2) regulates mitochondrial Complex I activity to suppress OXPHOS and maintain pluripotency; (3) acts as an endosomal scaffold for STAT3 interaction/activation to sustain JAK/STAT-dependent stem cell maintenance; (4) sequesters CSN5 via its OCIA domain to prevent p53 ubiquitination and degradation, thereby maintaining HSC quiescence; (5) functions downstream of ARF1-GTP in an endocytic axis that controls Notch trafficking and blood cell differentiation; and (6) balances mitochondrial and peroxisomal lipid metabolism, with its cleavage site at Cys38 targeted by the HCV NS3-4A protease."},"narrative":{"mechanistic_narrative":"OCIAD1 (Asrij) is a conserved, dually localized scaffold protein acting at endosomes and the inner mitochondrial membrane to coordinate organelle function with stem cell maintenance and differentiation [PMID:23972987, PMID:34034859]. At endosomes it provides a platform for STAT3 interaction and JAK/STAT-dependent pluripotency signaling [PMID:23972987] and controls Notch receptor trafficking, with loss causing Notch accumulation in sorting endosomes and aberrant blood cell (crystal cell) differentiation [PMID:22110713]; this endocytic axis operates downstream of activated ARF1-GTP, which physically binds OCIAD1 and regulates its levels [PMID:24707047, PMID:33433647]. At the inner mitochondrial membrane OCIAD1 assembles with supramolecular prohibitin complexes to support Complex III biogenesis by enabling IMMP2L-mediated processing of the catalytic subunit CYC1 [PMID:34034859] and to protect the TIMM17A variant of the TIM23 import translocase from YME1L-mediated degradation [PMID:39630581]. It additionally restrains Complex I activity and oxidative phosphorylation to maintain pluripotency, since Complex I inhibition rescues the differentiation defects of OCIAD1 loss [PMID:29937147], and it acts at the mitochondria–peroxisome interface to balance lipid metabolism, with knockout cells losing peroxisomal proteins and ether phospholipids while accumulating mitochondrial β-oxidation enzymes [PMID:40211913]. Through its conserved OCIA domain OCIAD1 sequesters the COP9 signalosome subunit CSN5 to block p53 ubiquitination and degradation, thereby sustaining hematopoietic stem cell quiescence [PMID:30952670]. Loss of OCIAD1 in HSCs produces convergent organelle dysfunction—damaged mitochondria with elevated ROS, impaired endosomal trafficking, and reduced proteasome activity—that is reversible by pharmacological correction [PMID:35289070]. OCIAD1 is cleaved at Cys38 by the HCV NS3-4A protease, a selectivity determined by sequence around the scissile site and the adjacent transmembrane segment [PMID:32697788].","teleology":[{"year":2003,"claim":"Established the existence and basal localization of OCIAD1/Asrij, defining it as a conserved transmembrane protein of the endo-lysosomal system expressed in stem cells and embryos.","evidence":"Subcellular fractionation and localization imaging in mouse ES cells and embryos","pmids":["12889067"],"confidence":"Medium","gaps":["No functional perturbation","Molecular activity undefined","Mitochondrial localization not yet detected"]},{"year":2011,"claim":"Showed OCIAD1 has a functional role in vesicular trafficking, linking it to Notch receptor sorting and blood cell differentiation rather than being a passive endosomal resident.","evidence":"Drosophila asrij null mutants with endosomal marker imaging and in vitro trafficking assays","pmids":["22110713"],"confidence":"High","gaps":["Direct cargo-binding mechanism unresolved","How OCIAD1 selects endosomal subcompartments unknown"]},{"year":2013,"claim":"Identified an endosomal signaling scaffold function by showing OCIAD1 binds STAT3 and dose-dependently tunes JAK/STAT signaling for stem cell maintenance.","evidence":"Co-IP, colocalization, and cross-species genetic gain/loss-of-function with rescue in mouse ESCs and Drosophila HSCs","pmids":["23972987"],"confidence":"High","gaps":["Whether OCIAD1 directly activates or just localizes STAT3 is unclear","Structural basis of the interaction unknown"]},{"year":2014,"claim":"Placed OCIAD1 in a defined signaling hierarchy by showing ARF1-GTP binds OCIAD1 and acts upstream in endocytic control of Notch trafficking and hematopoiesis.","evidence":"Genetic epistasis with ARF1 GEF/GAP manipulation, interaction assay, and Notch trafficking imaging","pmids":["24707047"],"confidence":"High","gaps":["Direct vs indirect ARF1 binding not resolved here","Downstream effectors between OCIAD1 and Notch sorting unidentified"]},{"year":2017,"claim":"Extended the ARF1-Asrij axis to innate immunity, distinguishing OCIAD1-dependent from ARF1-independent control of melanization and antimicrobial peptide pathways.","evidence":"Drosophila genetic loss-of-function with AMP/phenoloxidase, ubiquitination, and infection survival assays","pmids":["28273919"],"confidence":"Medium","gaps":["Molecular link to Cactus ubiquitination unresolved","Single model organism"]},{"year":2018,"claim":"Defined a mitochondrial function by showing OCIAD1 interacts with Complex I and restrains OXPHOS to preserve pluripotency.","evidence":"Co-IP, live-cell OXPHOS assays, CRISPR knockout, and Complex I inhibitor rescue in human pluripotent stem cells","pmids":["29937147"],"confidence":"High","gaps":["Whether OCIAD1 directly assembles into Complex I unknown","Mechanism of activity suppression unresolved"]},{"year":2019,"claim":"Resolved a molecular mechanism for stem cell maintenance: OCIAD1 sequesters CSN5 via its OCIA domain to stabilize p53 and enforce HSC quiescence.","evidence":"Domain-specific Co-IP, ubiquitination assay, asrij knockout mouse, Nutlin-3 rescue, and transplantation","pmids":["30952670"],"confidence":"High","gaps":["How endosomal/mitochondrial OCIAD1 pools relate to CSN5 sequestration unclear","Structural definition of OCIA-domain binding lacking"]},{"year":2020,"claim":"Mapped OCIAD1 as a host substrate of the HCV NS3-4A protease, defining the Cys38 scissile site and the determinants of protease selectivity.","evidence":"SILAC proteomics, replicon and cell-culture HCV systems, patient liver biopsies, and domain-swapping mutagenesis","pmids":["32697788"],"confidence":"High","gaps":["Functional consequence of cleavage for the host not established","Fate of cleavage fragments unknown"]},{"year":2021,"claim":"Established OCIAD1 as an inner mitochondrial membrane prohibitin-associated factor required for Complex III biogenesis through IMMP2L-mediated CYC1 processing.","evidence":"Genome-wide CRISPRi screen, fractionation, Co-IP, and CYC1 processing/Complex III assembly assays","pmids":["34034859"],"confidence":"High","gaps":["Whether OCIAD1 directly presents CYC1 to IMMP2L unknown","Stoichiometry within prohibitin assemblies undefined"]},{"year":2021,"claim":"Connected OCIAD1 to mitochondrial dynamics, showing its loss elongates mitochondria and that it genetically interacts with Drp1 and Marf to control differentiation.","evidence":"Live imaging of mitochondrial dynamics and genetic epistasis in Drosophila hemocytes and OCIAD1 KO hESCs","pmids":["34295888"],"confidence":"Medium","gaps":["Direct interaction with fission/fusion machinery untested","Causal order between dynamics and Notch defects unclear"]},{"year":2021,"claim":"Confirmed a direct OCIAD1-ARF1 physical interaction using purified components, validating the in vivo epistasis at the biochemical level.","evidence":"Protein complementation assay with bacterially purified recombinant proteins; sophorolipid-aided solubilization","pmids":["33433647"],"confidence":"Medium","gaps":["No structure obtained","Functional follow-up limited in this study"]},{"year":2022,"claim":"Demonstrated that OCIAD1 integrates mitochondrial, endosomal, and proteasomal organelle health in HSCs, with pharmacological and LPA-driven rescue of aging phenotypes.","evidence":"asrij knockout mouse with mitochondrial/ROS, trafficking marker, and proteasome assays plus pharmacological and LPA rescue in aged mice","pmids":["35289070"],"confidence":"High","gaps":["Whether organelle defects are independent or sequential unresolved","Primary versus secondary effects not separated"]},{"year":2024,"claim":"Refined the mitochondrial role by showing OCIAD1, with prohibitins, protects the TIMM17A variant of the TIM23 import translocase from YME1L proteolysis, with reciprocal regulation by TIM23 status.","evidence":"Co-IP of OCIAD1-prohibitin-TIM23, genetic depletion, YME1L protease assay, and TIM23 stability assays","pmids":["39630581"],"confidence":"High","gaps":["Mechanism distinguishing TIMM17A from TIMM17B protection unclear","How TIM23 status feeds back to OCIAD1 levels undefined"]},{"year":2025,"claim":"Positioned OCIAD1 at the mitochondria-peroxisome interface balancing lipid metabolism, linking its loss to peroxisomal protein loss and shifted ether-lipid and β-oxidation profiles.","evidence":"Lipidomics and proteomics of OCIAD1 KO cells, proximity-labeling meta-analysis, and peroxisome morphology imaging","pmids":["40211913"],"confidence":"Medium","gaps":["No direct enzymatic reconstitution with FAR1/ABCD3","Mechanism of peroxisomal protein loss unresolved"]},{"year":2025,"claim":"Implicated OCIAD1 as a driver of neuroinflammatory microglial states in Alzheimer's models via STAT3/NF-κB signaling, with depletion reducing plaque load.","evidence":"asrij knockout in APP/PS1 mice with microglial RNA-seq, flow cytometry, pathway activation assays, and behavioral testing","pmids":["40114191"],"confidence":"Medium","gaps":["Cell-intrinsic mechanism in microglia not dissected","Relationship to mitochondrial/endosomal functions unclear"]},{"year":null,"claim":"How OCIAD1 physically partitions between its endosomal scaffolding and inner-mitochondrial membrane roles, and whether one biochemical activity underlies both, remains unresolved.","evidence":"No study in the corpus reconciles the dual localization through a unifying molecular mechanism or structure","pmids":[],"confidence":"Low","gaps":["No structural model of OCIAD1","No defined catalytic activity","Determinants of dual targeting unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,8,12,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8,16]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7,12,13,16,17]},{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,12,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[12,16]}],"complexes":["prohibitin complex","TIM23 translocase (TIMM17A variant)","mitochondrial Complex III","mitochondrial Complex I"],"partners":["STAT3","ARF1","CSN5","BCL2","PHB","TIMM17A","YME1L","IMMP2L"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NX40","full_name":"OCIA domain-containing protein 1","aliases":["Ovarian cancer immunoreactive antigen domain containing 1","Ovarian carcinoma immunoreactive antigen"],"length_aa":245,"mass_kda":27.6,"function":"Maintains stem cell potency (By similarity). Increases STAT3 phosphorylation and controls ERK phosphorylation (By similarity). May act as a scaffold, increasing STAT3 recruitment onto endosomes (By similarity). Involved in integrin-mediated cancer cell adhesion and colony formation in ovarian cancer (PubMed:20515946)","subcellular_location":"Endosome","url":"https://www.uniprot.org/uniprotkb/Q9NX40/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OCIAD1","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OCIAD1","total_profiled":1310},"omim":[{"mim_id":"619633","title":"OCIA DOMAIN-CONTAINING PROTEIN 2; OCIAD2","url":"https://www.omim.org/entry/619633"},{"mim_id":"619596","title":"OCIA DOMAIN-CONTAINING PROTEIN 1; OCIAD1","url":"https://www.omim.org/entry/619596"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OCIAD1"},"hgnc":{"alias_symbol":["FLJ20455","TPA018","OCIA","Asrij"],"prev_symbol":[]},"alphafold":{"accession":"Q9NX40","domains":[{"cath_id":"-","chopping":"51-104","consensus_level":"medium","plddt":82.4226,"start":51,"end":104}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NX40","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NX40-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NX40-F1-predicted_aligned_error_v6.png","plddt_mean":65.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OCIAD1","jax_strain_url":"https://www.jax.org/strain/search?query=OCIAD1"},"sequence":{"accession":"Q9NX40","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NX40.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NX40/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NX40"}},"corpus_meta":[{"pmid":"24707047","id":"PMC_24707047","title":"ARF1-GTP regulates Asrij to provide endocytic control of Drosophila blood cell homeostasis.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24707047","citation_count":43,"is_preprint":false},{"pmid":"23972987","id":"PMC_23972987","title":"Conserved regulation of the Jak/STAT pathway by the endosomal protein asrij maintains stem cell potency.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23972987","citation_count":42,"is_preprint":false},{"pmid":"22110713","id":"PMC_22110713","title":"Asrij maintains the stem cell niche and controls differentiation during Drosophila lymph gland hematopoiesis.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22110713","citation_count":36,"is_preprint":false},{"pmid":"34034859","id":"PMC_34034859","title":"Genome-wide CRISPRi screening identifies OCIAD1 as a prohibitin client and regulatory determinant of mitochondrial Complex III assembly in human cells.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34034859","citation_count":33,"is_preprint":false},{"pmid":"30952670","id":"PMC_30952670","title":"Asrij/OCIAD1 suppresses CSN5-mediated p53 degradation and maintains mouse hematopoietic stem cell quiescence.","date":"2019","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/30952670","citation_count":30,"is_preprint":false},{"pmid":"29937147","id":"PMC_29937147","title":"OCIAD1 Controls Electron Transport Chain Complex I Activity to Regulate Energy Metabolism in Human Pluripotent Stem Cells.","date":"2018","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29937147","citation_count":24,"is_preprint":false},{"pmid":"18328549","id":"PMC_18328549","title":"Ovarian cancer immuno-reactive antigen domain containing 1 (OCIAD1), a key player in ovarian cancer cell adhesion.","date":"2008","source":"Gynecologic 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Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/12889067","citation_count":14,"is_preprint":false},{"pmid":"39630581","id":"PMC_39630581","title":"OCIAD1 and prohibitins regulate the stability of the TIM23 protein translocase.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39630581","citation_count":13,"is_preprint":false},{"pmid":"34295888","id":"PMC_34295888","title":"A Conserved Role for Asrij/OCIAD1 in Progenitor Differentiation and Lineage Specification Through Functional Interaction With the Regulators of Mitochondrial Dynamics.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34295888","citation_count":12,"is_preprint":false},{"pmid":"35289070","id":"PMC_35289070","title":"Organelle dysfunction upon asrij depletion causes aging-like changes in mouse hematopoietic stem cells.","date":"2022","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/35289070","citation_count":11,"is_preprint":false},{"pmid":"40114191","id":"PMC_40114191","title":"Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer's disease mouse model.","date":"2025","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/40114191","citation_count":8,"is_preprint":false},{"pmid":"12690451","id":"PMC_12690451","title":"Drosophila asrij is expressed in pole cells, trachea and hemocytes.","date":"2003","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/12690451","citation_count":8,"is_preprint":false},{"pmid":"32697788","id":"PMC_32697788","title":"OCIAD1 is a host mitochondrial substrate of the hepatitis C virus NS3-4A protease.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32697788","citation_count":7,"is_preprint":false},{"pmid":"27345991","id":"PMC_27345991","title":"Generation of a heterozygous knockout human embryonic stem cell line for the OCIAD1 locus using CRISPR/CAS9 mediated targeting: BJNhem20-OCIAD1-CRISPR-39.","date":"2016","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27345991","citation_count":5,"is_preprint":false},{"pmid":"30923041","id":"PMC_30923041","title":"Proteomics of Asrij Perturbation in Drosophila Lymph Glands for Identification of New Regulators of Hematopoiesis.","date":"2019","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/30923041","citation_count":4,"is_preprint":false},{"pmid":"31221523","id":"PMC_31221523","title":"OCIAD1 promoted pancreatic ductal adenocarcinoma migration by regulating ATM.","date":"2019","source":"Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/31221523","citation_count":3,"is_preprint":false},{"pmid":"27345969","id":"PMC_27345969","title":"Generation of a heterozygous knockout human embryonic stem cell line for the OCIAD1 locus using CRISPR/CAS9 mediated targeting: BJNhem20-OCIAD1-CRISPR-20.","date":"2016","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27345969","citation_count":3,"is_preprint":false},{"pmid":"33433647","id":"PMC_33433647","title":"Expression, Purification and Crystallization of Asrij, A Novel Scaffold Transmembrane Protein.","date":"2021","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/33433647","citation_count":2,"is_preprint":false},{"pmid":"40211913","id":"PMC_40211913","title":"Integrated proteome and lipidome analyses place OCIAD1 at the mitochondria-peroxisome intersection balancing lipid metabolism.","date":"2025","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/40211913","citation_count":1,"is_preprint":false},{"pmid":"27345812","id":"PMC_27345812","title":"Generation of transgenic human embryonic stem cell line BJNhem20-OCIAD1-OV.","date":"2016","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27345812","citation_count":1,"is_preprint":false},{"pmid":"41043641","id":"PMC_41043641","title":"Asrij/OCIAD1 expression delineates functionally distinct hematopoietic stem cells in the bone marrow.","date":"2025","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/41043641","citation_count":0,"is_preprint":false},{"pmid":"27345997","id":"PMC_27345997","title":"Generation of a transgenic human embryonic stem cell line ectopically expressing the endosomal protein Asrij that regulates pluripotency in mouse embryonic stem cells: BJNhem20-Asrij.","date":"2016","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27345997","citation_count":0,"is_preprint":false},{"pmid":"27345976","id":"PMC_27345976","title":"Generation of OCIAD1 inducible overexpression human embryonic stem cell line: BJNhem20-OCIAD1-Tet-On.","date":"2016","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27345976","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.15.623757","title":"Integrated proteome and lipidome analyses place OCIAD1 at mitochondria-peroxisome intersection balancing lipid metabolism","date":"2024-11-15","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.15.623757","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.18.670767","title":"Integrated QTL mapping and CRISPR screening in pooled iPSC-derived microglia reveals genetic drivers of neurodegenerative risk","date":"2025-08-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.18.670767","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15803,"output_tokens":4922,"usd":0.060619,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13235,"output_tokens":4842,"usd":0.093613,"stage2_stop_reason":"end_turn"},"total_usd":0.154232,"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\": 2003,\n      \"finding\": \"Asrij/OCIAD1 encodes a novel conserved predicted transmembrane protein of 247 amino acids that localizes to lysosomes and endosomes, as determined by subcellular fractionation and localization studies in mouse embryonic stem cells and during development.\",\n      \"method\": \"Subcellular localization (lysosomes/endosomes) by direct imaging/fractionation; expression analysis in ES cells and embryos\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment, replicated in multiple tissue contexts in a single study, but no functional mutagenesis\",\n      \"pmids\": [\"12889067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Drosophila Asrij localizes to a subset of endocytic vesicles and is required for proper Notch trafficking; loss of asrij causes accumulation of Notch in sorting endosomes and increased crystal cell differentiation, indicating Asrij regulates Notch signaling through endosomal trafficking.\",\n      \"method\": \"Genetic loss-of-function (asrij null mutants), immunostaining of endosomal markers, in vitro fluorescent probe trafficking assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, imaging, in vitro trafficking assay), replicated in multiple contexts within the study\",\n      \"pmids\": [\"22110713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Asrij/OCIAD1 is an endosomal protein that dose-dependently modulates JAK/STAT signaling to maintain stem cell pluripotency; STAT3 colocalizes with Asrij in endosomes and interacts with it biochemically, suggesting Asrij provides an endosomal scaffold for STAT3 activation.\",\n      \"method\": \"Co-immunoprecipitation (biochemical interaction), colocalization imaging (endosomal compartment), genetic gain/loss-of-function in mouse ESCs and Drosophila HSCs, cross-species rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical interaction, colocalization, genetic epistasis across two species with rescue experiment\",\n      \"pmids\": [\"23972987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Activated ARF1 (ARF1-GTP) physically interacts with Asrij and regulates its levels in blood cells; perturbation of ARF1 activation leads to aberrant Notch trafficking with Notch intracellular domain stalled in sorting endosomes, placing ARF1 upstream of Asrij in endocytic control of hematopoiesis.\",\n      \"method\": \"Genetic epistasis (ARF1 knockdown, GEF/GAP manipulation), co-immunoprecipitation/interaction assay, Notch trafficking analysis by immunostaining\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple alleles, interaction assay, trafficking readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24707047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OCIAD1 overexpression in ovarian cancer cells increases LPA-induced cell adhesion to collagen I and laminin 10/11, and this effect is not blocked by PKC or PI3K inhibitors, indicating OCIAD1 promotes cell adhesion through a PKC/PI3K-independent mechanism.\",\n      \"method\": \"Overexpression and knockdown in HEY ovarian cancer cells, cell adhesion assay with pharmacological inhibitors (LY294002, GF109203X)\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain- and loss-of-function with defined cellular phenotype and pathway exclusion, single lab\",\n      \"pmids\": [\"18328549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LPA induces OCIAD1 serine phosphorylation within 2 hours and upregulates OCIAD1 expression via the MKK6/p38 MAPK pathway; OCIAD1 knockdown inhibits LPA-induced adhesion to collagen I and laminin 10/11 and specifically to alpha2, alpha5, alphaV, and beta1 integrins; proteomic studies show OCIAD1 is physically associated with alpha-actin 4 and beta-actin, indicating a role in cytoskeletal regulation.\",\n      \"method\": \"LPA stimulation assay, serine phosphorylation detection, p38 inhibitor (pharmacological), MKK6 transfection, knockdown, integrin-specific adhesion assay, co-immunoprecipitation/proteomics (OCIAD1–actin interaction)\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (phosphorylation, pharmacology, knockdown, proteomics), single lab\",\n      \"pmids\": [\"20515946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The ARF1-Asrij endosomal axis regulates the cellular immune response by controlling crystal cell melanization and phenoloxidase activity, and suppresses Toll pathway anti-microbial peptides by regulating ubiquitination of the Toll inhibitor Cactus; Asrij (but not ARF1) is required for Imd pathway AMP production.\",\n      \"method\": \"Genetic loss-of-function (ARF1 and asrij mutants), AMP and phenoloxidase activity assays, ubiquitination analysis, infection survival assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple pathway readouts, single lab\",\n      \"pmids\": [\"28273919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OCIAD1 interacts with mitochondrial Complex I and regulates its activity; OCIAD1 depletion in human pluripotent stem cells increases oxidative phosphorylation (OXPHOS), and pharmacological inhibition of Complex I rescues the differentiation defects caused by OCIAD1 loss, placing OCIAD1 as a regulator of mitochondrial Complex I activity to maintain pluripotency.\",\n      \"method\": \"Co-immunoprecipitation (OCIAD1-Complex I interaction), energy metabolic assays (live cell OXPHOS), CRISPR/Cas9 knockout, pharmacological rescue (Complex I inhibitor)\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical interaction, functional metabolic assay, genetic KO, and pharmacological epistasis in one study\",\n      \"pmids\": [\"29937147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Asrij/OCIAD1 sequesters CSN5 (COP9 signalosome subunit 5) via its conserved OCIA domain, preventing CSN5-mediated p53 ubiquitination and degradation; loss of Asrij in mouse HSCs leads to increased polyubiquitinated proteins and p53 degradation, and Nutlin-3 treatment (p53 stabilization) restores normal HSPC frequencies in asrij knockout mice.\",\n      \"method\": \"Co-immunoprecipitation (Asrij-CSN5 interaction via OCIA domain), ubiquitination assay, asrij knockout mouse model, pharmacological rescue (Nutlin-3), transplantation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific interaction, in vivo KO phenotype, pharmacological rescue and molecular mechanism in a single rigorous study\",\n      \"pmids\": [\"30952670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OCIAD1 regulates ATM expression/function in pancreatic ductal adenocarcinoma cells to promote cell migration; OCIAD1 downregulation inhibits migration and is associated with increased ATM.\",\n      \"method\": \"Knockdown/overexpression in PDAC cell lines, migration assay, gene chip correlation analysis\",\n      \"journal\": \"Pancreatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single functional assay, limited mechanistic resolution\",\n      \"pmids\": [\"31221523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HCV NS3-4A protease cleaves OCIAD1 at Cys38, near a predicted transmembrane segment; cleavage occurs in heterologous systems, HCV replicons, cell-culture HCV, and human liver biopsies from chronic HCV patients; domain-swapping experiments show that the sequence surrounding Cys38 and the transmembrane segment determine substrate selectivity for NS3-4A.\",\n      \"method\": \"Quantitative proteomics (SILAC-MS), heterologous expression cleavage assay, replicon system, cell culture HCV system, patient liver biopsies, domain-swapping mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cleavage site identified by mutagenesis and domain swapping, validated in multiple independent systems including patient material\",\n      \"pmids\": [\"32697788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Elevated OCIAD1 interacts with BCL-2 to impair mitochondrial function in neurons; OCIAD1 levels are increased by Aβ/GSK-3β signaling, and elevated OCIAD1 increases neuronal susceptibility to AD pathological challenges.\",\n      \"method\": \"Co-immunoprecipitation (OCIAD1-BCL-2 interaction), mitochondrial function assays, overexpression in neuronal cells, bioinformatics-guided candidate identification\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — biochemical interaction and functional assay, single lab, multiple methods but limited genetic validation\",\n      \"pmids\": [\"31931285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OCIAD1 is an inner mitochondrial membrane protein that forms a complex with supramolecular prohibitin assemblies and is required for normal steady-state levels of mitochondrial Complex III and for proteolytic processing of the catalytic subunit cytochrome c (CYC1) by the IMMP2L protease; in OCIAD1-depleted mitochondria, unprocessed CYC1 is hemylated and incorporated into Complex III.\",\n      \"method\": \"Genome-wide CRISPRi screen, CRISPRi depletion, mitochondrial fractionation, co-immunoprecipitation (OCIAD1-prohibitin complex), Complex III assembly assay, CYC1 processing assay, proteomics\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genome-wide functional screen, biochemical reconstitution of complex, multiple orthogonal methods including fractionation, interaction, and substrate processing assays in one study\",\n      \"pmids\": [\"34034859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Asrij/OCIAD1 localizes to mitochondria of larval blood cells and its depletion causes elongated mitochondria and reduced mitochondrial dynamics; genetic interaction studies show Asrij synergizes with fission regulator Drp1 and fusion regulator Marf/Mitofusin to control crystal cell differentiation and Notch signaling in Drosophila progenitors.\",\n      \"method\": \"Live imaging of mitochondrial dynamics (knockdown hemocytes and OCIAD1 KO hESCs), genetic epistasis (Drp1 and Marf knockdown with asrij depletion), Notch signaling readout\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with functional consequence, genetic epistasis in two model systems, single lab\",\n      \"pmids\": [\"34295888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Asrij/OCIAD1 physically interacts with ARF1 as confirmed by a protein complementation assay using bacterially expressed purified proteins; sophorolipids improve solubility and monodispersibility of purified Asrij membrane protein.\",\n      \"method\": \"Protein complementation assay (in vitro with purified recombinant proteins), heterologous expression and purification, crystallization trials\",\n      \"journal\": \"The Journal of membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted physical interaction with purified components, but single lab and limited functional follow-up in this study\",\n      \"pmids\": [\"33433647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In asrij knockout mouse HSCs, organelle dysfunction occurs: damaged mitochondria with elevated ROS, impaired endosomal trafficking (increased cleaved Notch1, reduced Rab5), and reduced 26S proteasome activity; pharmacological correction of mitochondrial and proteasome activity restores HSC and myeloid cell frequencies, and LPA-induced Asrij upregulation in aged mice rescues these organelle functions.\",\n      \"method\": \"asrij knockout mouse, mitochondrial function assay, ROS measurement, endosomal trafficking markers (Notch1, Rab5), proteasome activity assay, pharmacological rescue, LPA stimulation in aged mice\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple organelle functional readouts, pharmacological epistasis, and in vivo rescue, multiple orthogonal methods\",\n      \"pmids\": [\"35289070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OCIAD1 assembles with the prohibitin complex to protect the TIMM17A variant of the mitochondrial TIM23 translocase from degradation by the YME1L protease; prohibitins are required to stabilize both TIMM17A- and TIMM17B-containing TIM23 variants; OCIAD1 expression is in turn regulated by TIM23 complex status.\",\n      \"method\": \"Co-immunoprecipitation (OCIAD1-prohibitin-TIM23 complex), genetic depletion of OCIAD1 and prohibitins, protease (YME1L) activity assay, TIM23 stability assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal complex interaction, identification of specific protease (YME1L) and substrate variant (TIMM17A), multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"39630581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OCIAD1 knockout cells show extensive lipidome rearrangement including decreased ether phospholipids and phospholipids with odd numbers of carbons, associated with global loss of peroxisomal proteins and aberrant peroxisomal morphology, and increased mitochondrial fatty acid β-oxidation proteins; OCIAD1 is proposed to act at the mitochondria-peroxisome interface to balance lipid metabolism, with direct impact on FAR1 and ABCD3 enzymes.\",\n      \"method\": \"Mass spectrometry-based lipidomics and proteomics (mitochondrial fraction and whole cell) of OCIAD1 KO cells, proximity labeling meta-analysis, peroxisome morphology imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative multi-omic approach (proteomics + lipidomics) with morphological validation, single lab, no direct enzymatic reconstitution\",\n      \"pmids\": [\"40211913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Asrij depletion in APP/PS1 AD mice reduces STAT3 and NF-κB activation in microglia, increases mitochondrial activity, and impedes acquisition of the pro-inflammatory disease-associated microglia (DAM) state; loss of Asrij reduces proinflammatory cytokine levels and Aβ plaque load, positioning Asrij as a promoter of neuroinflammatory DAM signaling.\",\n      \"method\": \"asrij knockout in APP/PS1 mice, flow cytometry, RNA sequencing of AD microglia, confocal microscopy, immunohistochemistry, STAT3/NF-κB activation assay, mitochondrial activity assay, behavioral testing\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO with transcriptomic and biochemical pathway readouts, single lab, multiple methods\",\n      \"pmids\": [\"40114191\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OCIAD1/Asrij is a conserved inner mitochondrial membrane (and endosomal) scaffold protein that: (1) assembles with prohibitin complexes to stabilize Complex III assembly by chaperoning CYC1 processing via IMMP2L, and to protect the TIMM17A variant of the TIM23 translocase from YME1L-mediated degradation; (2) regulates mitochondrial Complex I activity to suppress OXPHOS and maintain pluripotency; (3) acts as an endosomal scaffold for STAT3 interaction/activation to sustain JAK/STAT-dependent stem cell maintenance; (4) sequesters CSN5 via its OCIA domain to prevent p53 ubiquitination and degradation, thereby maintaining HSC quiescence; (5) functions downstream of ARF1-GTP in an endocytic axis that controls Notch trafficking and blood cell differentiation; and (6) balances mitochondrial and peroxisomal lipid metabolism, with its cleavage site at Cys38 targeted by the HCV NS3-4A protease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OCIAD1 (Asrij) is a conserved, dually localized scaffold protein acting at endosomes and the inner mitochondrial membrane to coordinate organelle function with stem cell maintenance and differentiation [#2, #12]. At endosomes it provides a platform for STAT3 interaction and JAK/STAT-dependent pluripotency signaling [#2] and controls Notch receptor trafficking, with loss causing Notch accumulation in sorting endosomes and aberrant blood cell (crystal cell) differentiation [#1]; this endocytic axis operates downstream of activated ARF1-GTP, which physically binds OCIAD1 and regulates its levels [#3, #14]. At the inner mitochondrial membrane OCIAD1 assembles with supramolecular prohibitin complexes to support Complex III biogenesis by enabling IMMP2L-mediated processing of the catalytic subunit CYC1 [#12] and to protect the TIMM17A variant of the TIM23 import translocase from YME1L-mediated degradation [#16]. It additionally restrains Complex I activity and oxidative phosphorylation to maintain pluripotency, since Complex I inhibition rescues the differentiation defects of OCIAD1 loss [#7], and it acts at the mitochondria–peroxisome interface to balance lipid metabolism, with knockout cells losing peroxisomal proteins and ether phospholipids while accumulating mitochondrial β-oxidation enzymes [#17]. Through its conserved OCIA domain OCIAD1 sequesters the COP9 signalosome subunit CSN5 to block p53 ubiquitination and degradation, thereby sustaining hematopoietic stem cell quiescence [#8]. Loss of OCIAD1 in HSCs produces convergent organelle dysfunction—damaged mitochondria with elevated ROS, impaired endosomal trafficking, and reduced proteasome activity—that is reversible by pharmacological correction [#15]. OCIAD1 is cleaved at Cys38 by the HCV NS3-4A protease, a selectivity determined by sequence around the scissile site and the adjacent transmembrane segment [#10].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the existence and basal localization of OCIAD1/Asrij, defining it as a conserved transmembrane protein of the endo-lysosomal system expressed in stem cells and embryos.\",\n      \"evidence\": \"Subcellular fractionation and localization imaging in mouse ES cells and embryos\",\n      \"pmids\": [\"12889067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional perturbation\", \"Molecular activity undefined\", \"Mitochondrial localization not yet detected\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed OCIAD1 has a functional role in vesicular trafficking, linking it to Notch receptor sorting and blood cell differentiation rather than being a passive endosomal resident.\",\n      \"evidence\": \"Drosophila asrij null mutants with endosomal marker imaging and in vitro trafficking assays\",\n      \"pmids\": [\"22110713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cargo-binding mechanism unresolved\", \"How OCIAD1 selects endosomal subcompartments unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified an endosomal signaling scaffold function by showing OCIAD1 binds STAT3 and dose-dependently tunes JAK/STAT signaling for stem cell maintenance.\",\n      \"evidence\": \"Co-IP, colocalization, and cross-species genetic gain/loss-of-function with rescue in mouse ESCs and Drosophila HSCs\",\n      \"pmids\": [\"23972987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OCIAD1 directly activates or just localizes STAT3 is unclear\", \"Structural basis of the interaction unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed OCIAD1 in a defined signaling hierarchy by showing ARF1-GTP binds OCIAD1 and acts upstream in endocytic control of Notch trafficking and hematopoiesis.\",\n      \"evidence\": \"Genetic epistasis with ARF1 GEF/GAP manipulation, interaction assay, and Notch trafficking imaging\",\n      \"pmids\": [\"24707047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect ARF1 binding not resolved here\", \"Downstream effectors between OCIAD1 and Notch sorting unidentified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the ARF1-Asrij axis to innate immunity, distinguishing OCIAD1-dependent from ARF1-independent control of melanization and antimicrobial peptide pathways.\",\n      \"evidence\": \"Drosophila genetic loss-of-function with AMP/phenoloxidase, ubiquitination, and infection survival assays\",\n      \"pmids\": [\"28273919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link to Cactus ubiquitination unresolved\", \"Single model organism\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a mitochondrial function by showing OCIAD1 interacts with Complex I and restrains OXPHOS to preserve pluripotency.\",\n      \"evidence\": \"Co-IP, live-cell OXPHOS assays, CRISPR knockout, and Complex I inhibitor rescue in human pluripotent stem cells\",\n      \"pmids\": [\"29937147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OCIAD1 directly assembles into Complex I unknown\", \"Mechanism of activity suppression unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved a molecular mechanism for stem cell maintenance: OCIAD1 sequesters CSN5 via its OCIA domain to stabilize p53 and enforce HSC quiescence.\",\n      \"evidence\": \"Domain-specific Co-IP, ubiquitination assay, asrij knockout mouse, Nutlin-3 rescue, and transplantation\",\n      \"pmids\": [\"30952670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How endosomal/mitochondrial OCIAD1 pools relate to CSN5 sequestration unclear\", \"Structural definition of OCIA-domain binding lacking\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped OCIAD1 as a host substrate of the HCV NS3-4A protease, defining the Cys38 scissile site and the determinants of protease selectivity.\",\n      \"evidence\": \"SILAC proteomics, replicon and cell-culture HCV systems, patient liver biopsies, and domain-swapping mutagenesis\",\n      \"pmids\": [\"32697788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of cleavage for the host not established\", \"Fate of cleavage fragments unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established OCIAD1 as an inner mitochondrial membrane prohibitin-associated factor required for Complex III biogenesis through IMMP2L-mediated CYC1 processing.\",\n      \"evidence\": \"Genome-wide CRISPRi screen, fractionation, Co-IP, and CYC1 processing/Complex III assembly assays\",\n      \"pmids\": [\"34034859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OCIAD1 directly presents CYC1 to IMMP2L unknown\", \"Stoichiometry within prohibitin assemblies undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected OCIAD1 to mitochondrial dynamics, showing its loss elongates mitochondria and that it genetically interacts with Drp1 and Marf to control differentiation.\",\n      \"evidence\": \"Live imaging of mitochondrial dynamics and genetic epistasis in Drosophila hemocytes and OCIAD1 KO hESCs\",\n      \"pmids\": [\"34295888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction with fission/fusion machinery untested\", \"Causal order between dynamics and Notch defects unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed a direct OCIAD1-ARF1 physical interaction using purified components, validating the in vivo epistasis at the biochemical level.\",\n      \"evidence\": \"Protein complementation assay with bacterially purified recombinant proteins; sophorolipid-aided solubilization\",\n      \"pmids\": [\"33433647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure obtained\", \"Functional follow-up limited in this study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that OCIAD1 integrates mitochondrial, endosomal, and proteasomal organelle health in HSCs, with pharmacological and LPA-driven rescue of aging phenotypes.\",\n      \"evidence\": \"asrij knockout mouse with mitochondrial/ROS, trafficking marker, and proteasome assays plus pharmacological and LPA rescue in aged mice\",\n      \"pmids\": [\"35289070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether organelle defects are independent or sequential unresolved\", \"Primary versus secondary effects not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the mitochondrial role by showing OCIAD1, with prohibitins, protects the TIMM17A variant of the TIM23 import translocase from YME1L proteolysis, with reciprocal regulation by TIM23 status.\",\n      \"evidence\": \"Co-IP of OCIAD1-prohibitin-TIM23, genetic depletion, YME1L protease assay, and TIM23 stability assays\",\n      \"pmids\": [\"39630581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing TIMM17A from TIMM17B protection unclear\", \"How TIM23 status feeds back to OCIAD1 levels undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned OCIAD1 at the mitochondria-peroxisome interface balancing lipid metabolism, linking its loss to peroxisomal protein loss and shifted ether-lipid and β-oxidation profiles.\",\n      \"evidence\": \"Lipidomics and proteomics of OCIAD1 KO cells, proximity-labeling meta-analysis, and peroxisome morphology imaging\",\n      \"pmids\": [\"40211913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct enzymatic reconstitution with FAR1/ABCD3\", \"Mechanism of peroxisomal protein loss unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated OCIAD1 as a driver of neuroinflammatory microglial states in Alzheimer's models via STAT3/NF-κB signaling, with depletion reducing plaque load.\",\n      \"evidence\": \"asrij knockout in APP/PS1 mice with microglial RNA-seq, flow cytometry, pathway activation assays, and behavioral testing\",\n      \"pmids\": [\"40114191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic mechanism in microglia not dissected\", \"Relationship to mitochondrial/endosomal functions unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OCIAD1 physically partitions between its endosomal scaffolding and inner-mitochondrial membrane roles, and whether one biochemical activity underlies both, remains unresolved.\",\n      \"evidence\": \"No study in the corpus reconciles the dual localization through a unifying molecular mechanism or structure\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of OCIAD1\", \"No defined catalytic activity\", \"Determinants of dual targeting unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 8, 12, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005743\", \"supporting_discovery_ids\": [12, 16]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7, 12, 13, 16, 17]},\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 12, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12, 16]}\n    ],\n    \"complexes\": [\n      \"prohibitin complex\",\n      \"TIM23 translocase (TIMM17A variant)\",\n      \"mitochondrial Complex III\",\n      \"mitochondrial Complex I\"\n    ],\n    \"partners\": [\n      \"STAT3\",\n      \"ARF1\",\n      \"CSN5\",\n      \"BCL2\",\n      \"PHB\",\n      \"TIMM17A\",\n      \"YME1L\",\n      \"IMMP2L\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}