{"gene":"RETREG2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2021,"finding":"FAM134A (RETREG2) functions as an ER-phagy receptor that, upon autophagy induction or ER stress, induces ER fragmentation and subsequent lysosomal degradation. FAM134A maintains ER morphology in a LC3-interacting region (LIR)-dependent manner. Notably, FAM134A can act in a LIR-independent manner to compensate for loss of FAM134B and FAM134C in degrading pro-Collagen I as a shared ER-phagy substrate, whereas FAM134C cannot compensate for loss of its paralogues.","method":"Overexpression and knockout cell lines with global proteomic analysis, ER-phagy flux assays, LIR-mutant constructs, collagen I substrate degradation assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO lines, OE, proteomics, LIR mutagenesis, substrate assays) in a single rigorous study with functional validation","pmids":["34338405"],"is_preprint":false},{"year":2017,"finding":"FAM134A (RETREG2) is localized to the endoplasmic reticulum, and its depletion by RNAi impairs mitotic progression by affecting metaphase plate alignment and intracellular pressure generation, the latter through delocalization of cortical myosin II.","method":"Genome-scale RNAi screen with microcantilever-based single-cell mechanical phenotyping; protein localization by fluorescence microscopy; measurement of mitotic rounding force, pressure, and volume","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-scale RNAi screen with quantitative mechanical readouts and localization data, single study with two orthogonal methods but no rescue or mutagenesis","pmids":["29097687"],"is_preprint":false},{"year":2021,"finding":"FAM134B (the closest paralogue) preferentially binds the GABARAP subfamily of Atg8 proteins over the LC3 subfamily via its LIR motif plus a C-terminal helix, and structural analysis suggests these binding properties are conserved in FAM134A.","method":"Crystal structure of FAM134B-GABARAP complex; binding affinity measurements; inference extended to FAM134A by sequence/structural conservation analysis","journal":"FEBS open bio","confidence":"Low","confidence_rationale":"Tier 3 / Weak — structural and binding data are for FAM134B; FAM134A conservation is inferred, not directly tested","pmids":["34854256"],"is_preprint":false},{"year":2022,"finding":"FAM134C (a paralogue) is phosphorylated by casein kinase 2 (CK2) at residues flanking its LIR domain under fed conditions, reducing LC3-binding affinity and suppressing ER-phagy; mTORC1 inhibition during starvation limits CK2-mediated phosphorylation, thereby activating FAM134C-dependent ER-phagy. This phosphorylation-based activation mechanism is specific to FAM134C and not described for FAM134A.","method":"Phospho-mutagenesis, CK2 kinase assays, LC3 binding affinity measurements, FAM134C knockout mice, in vivo ER-phagy reporter","journal":"Science advances","confidence":"Low","confidence_rationale":"Tier 1 / Weak — rigorous mechanistic study but pertains directly to FAM134C paralogue; FAM134A is mentioned only for structural comparison and is not directly tested","pmids":["36044577"],"is_preprint":false},{"year":2024,"finding":"FAM134A (RETREG2) variants can accelerate degradation of misfolded α1-antitrypsin variant Z in iPSC-derived hepatocyte-like cells, while a specific FAM134A variant combined with an MTMR12 variant slows this degradation, implicating FAM134A-mediated ER-phagy as a modifier of hepatic proteotoxicity in α1-antitrypsin deficiency.","method":"Genomic sequencing of patient families; iPSC-derived hepatocyte-like cell assays measuring α1-antitrypsin variant Z degradation kinetics with patient-specific variants","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional testing of FAM134A variants in disease-relevant human cells with quantitative substrate degradation readout, single study","pmids":["38557779"],"is_preprint":false},{"year":2009,"finding":"MAG-2 (identified as FAM134A/RETREG2 in the lung cancer context) promotes invasion, mobility, and adherence of lung cancer cells, with overexpression upregulating MMP-2 and CD44 expression and increasing intracellular free calcium ion concentration, while knockdown reduces these metastatic properties.","method":"Gene transfection (overexpression) and RNAi (knockdown) in lung cancer cells; invasion/migration assays; RT-PCR and Western blot for MMP-2 and CD44; Fluo-3-AM calcium imaging","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — bidirectional gain/loss-of-function with multiple molecular readouts in a single lab; no independent replication","pmids":["19212629"],"is_preprint":false},{"year":2008,"finding":"MAG-2 (FAM134A/RETREG2) promotes lung cancer cell proliferation by increasing PCNA mRNA levels, downregulating p53 protein, and elevating intracellular cytoplasmic free calcium concentration; knockdown decreases calcium levels and restrains proliferation.","method":"Stable transfection of sense/antisense MAG-2 vectors in PLA801 cells; MTT proliferation assay; RT-PCR for PCNA; Western blot for p53; Fluo-3-AM calcium staining; cell cycle analysis","journal":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single study, multiple readouts but in a non-peer-reviewed Chinese journal with limited replication","pmids":["20735960"],"is_preprint":false},{"year":2024,"finding":"FAM134A and FAM134B are dispensable individually, but combined deletion of FAM134B and FAM134C (not FAM134A) in mice causes rapid neuromuscular degeneration and death, with loss of motor and sensory axons and expanded tubular ER with ladder-like appearance in long axons; FAM134A cannot compensate for combined FAM134B/FAM134C loss in axonal ER architecture.","method":"Single and combined knockout mice; neuromuscular phenotyping; electron microscopy of axonal ER morphology; histology of peripheral nervous system","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis with multiple KO combinations and ultrastructural readout; FAM134A's inability to compensate is a direct genetic finding, single study","pmids":["39039299"],"is_preprint":false},{"year":2025,"finding":"Ethanol reduces FAM134A expression in neuronal cells and mouse hippocampus through an epigenetic mechanism: ethanol metabolism suppresses SIRT1 activity, leading to increased H4K16 acetylation, enhanced BRD4 recruitment to the FAM134A promoter, and BRD4/G9a complex-mediated H3K9 dimethylation that blocks XBP1s-dependent transcription of FAM134A. BRD4 inhibition or FAM134A overexpression restores ER-phagy and prevents synaptic loss and neuronal death.","method":"ChIP assays for histone marks and BRD4/G9a at FAM134A promoter; SIRT1 activity assays; FAM134A overexpression rescue; BRD4 inhibitor treatment in cells and ethanol-fed mice; cognitive function testing","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal epigenetic and functional methods in vitro and in vivo, single lab study","pmids":["40959274"],"is_preprint":false},{"year":2003,"finding":"MAG-2 (subsequently identified as FAM134A/RETREG2) was identified as a gene with a 9-exon, 5.2 kb structure located on chromosome 2q35, showing higher expression in high-metastatic versus low-metastatic lung cancer cell sublines derived from the same parental line.","method":"Suppression subtractive hybridization (SSH) library construction and gene chip screening; sequencing and GenBank analysis; ORF and structural prediction","journal":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","confidence":"Low","confidence_rationale":"Tier 4 / Weak — initial identification by differential expression/sequencing with no direct functional experiment","pmids":["21310131"],"is_preprint":false}],"current_model":"RETREG2/FAM134A is an ER-resident protein that functions as an ER-phagy receptor, promoting ER fragmentation and lysosomal degradation upon autophagy induction or ER stress through its LIR motif; it can also act LIR-independently to degrade substrates such as pro-Collagen I and compensate for loss of FAM134B/FAM134C, though it cannot substitute for the combined FAM134B/FAM134C function in maintaining axonal tubular ER architecture in vivo; its expression is regulated epigenetically by a BRD4/G9a axis downstream of SIRT1, and in cancer cell contexts it has been shown to modulate intracellular calcium, MMP-2, CD44, and cell proliferation/invasion, though the mechanistic links between these cancer-related functions and its ER-phagy receptor role remain to be fully resolved."},"narrative":{"mechanistic_narrative":"RETREG2 (FAM134A) is an endoplasmic reticulum-resident ER-phagy receptor that drives ER fragmentation and lysosomal degradation of ER membrane upon autophagy induction or ER stress [PMID:34338405]. It maintains ER morphology through its LC3-interacting region (LIR), but can also act LIR-independently to compensate for loss of its paralogues FAM134B and FAM134C in degrading the shared ER-phagy substrate pro-Collagen I [PMID:34338405]. This receptor activity has disease relevance: RETREG2 variants modulate ER-phagy-mediated clearance of the misfolded α1-antitrypsin variant Z in iPSC-derived hepatocytes, positioning RETREG2 as a modifier of hepatic proteotoxicity in α1-antitrypsin deficiency [PMID:38557779]. RETREG2 expression is controlled epigenetically through a SIRT1–BRD4/G9a axis that regulates XBP1s-dependent transcription, and its loss compromises ER-phagy and promotes neuronal death, while its restoration is protective [PMID:40959274]. Beyond its canonical ER-phagy role, RETREG2 was independently characterized in lung cancer (as MAG-2) where it promotes proliferation and invasion in association with elevated intracellular calcium, MMP-2, and CD44 [PMID:19212629, PMID:20735960], and is required for normal mitotic progression and intracellular pressure generation [PMID:29097687]; how these activities connect to its ER-phagy receptor function is not resolved in the available corpus.","teleology":[{"year":2003,"claim":"Established the existence and genomic structure of the gene (then MAG-2) and its first functional association — differential expression correlating with metastatic potential — before any molecular role was known.","evidence":"Suppression subtractive hybridization and gene chip screening of metastatic lung cancer cell sublines","pmids":["21310131"],"confidence":"Low","gaps":["No direct functional experiment","Correlative expression only, no causal mechanism"]},{"year":2008,"claim":"Tested whether the gene actively drives a cancer phenotype, showing gain/loss of function alters proliferation alongside changes in PCNA, p53, and intracellular calcium.","evidence":"Sense/antisense stable transfection in PLA801 lung cancer cells with proliferation, RT-PCR, Western, and calcium imaging readouts","pmids":["20735960"],"confidence":"Low","gaps":["Single lab, non-peer-reviewed journal","Mechanism linking calcium to proliferation not defined","No connection yet to ER biology"]},{"year":2009,"claim":"Extended the cancer phenotype to invasion/metastasis, linking the gene to MMP-2, CD44, and intracellular calcium through bidirectional perturbation.","evidence":"Overexpression and RNAi in lung cancer cells with invasion/migration assays and molecular readouts","pmids":["19212629"],"confidence":"Medium","gaps":["No independent replication","Mechanistic link between the gene and MMP-2/CD44 induction unresolved","Relationship to later-defined ER-phagy role unknown"]},{"year":2017,"claim":"Localized the protein to the ER and revealed a role in cell division, where depletion impairs metaphase plate alignment and intracellular pressure via cortical myosin II delocalization.","evidence":"Genome-scale RNAi screen with microcantilever single-cell mechanical phenotyping and fluorescence localization","pmids":["29097687"],"confidence":"Medium","gaps":["No rescue or mutagenesis to confirm specificity","Mechanism connecting ER localization to mitotic pressure unclear","Not linked to ER-phagy function"]},{"year":2021,"claim":"Defined the protein's core molecular identity as a LIR-dependent ER-phagy receptor that fragments ER for lysosomal degradation, and uniquely can substitute LIR-independently for its paralogues in degrading pro-Collagen I.","evidence":"Knockout and overexpression cell lines, global proteomics, ER-phagy flux assays, LIR mutants, and collagen I substrate degradation assays","pmids":["34338405"],"confidence":"High","gaps":["Mechanism of LIR-independent substrate degradation undefined","Atg8-family binding preference not directly measured for this protein","No structural model"]},{"year":2024,"claim":"Demonstrated disease-relevant ER-phagy function, showing the protein's variants modify clearance of misfolded α1-antitrypsin variant Z in human hepatocytes.","evidence":"Patient family genomic sequencing and iPSC-derived hepatocyte degradation kinetics with patient-specific variants","pmids":["38557779"],"confidence":"Medium","gaps":["Single study","Molecular basis of variant effects on receptor activity not resolved","Interaction with MTMR12 variant mechanistically unexplained"]},{"year":2024,"claim":"Defined the in vivo functional boundary, establishing through genetic epistasis that this protein cannot compensate for combined FAM134B/FAM134C loss in maintaining axonal tubular ER architecture.","evidence":"Single and combined knockout mice with neuromuscular phenotyping and electron microscopy of axonal ER","pmids":["39039299"],"confidence":"Medium","gaps":["Why compensation fails in axons but succeeds for collagen is unexplained","Tissue-specific contribution of the protein not isolated","Single study"]},{"year":2025,"claim":"Identified an upstream regulatory axis controlling protein expression, showing a SIRT1–BRD4/G9a chromatin pathway gates XBP1s-dependent transcription and that restoring the protein rescues ER-phagy and neuronal survival.","evidence":"ChIP for histone marks and BRD4/G9a, SIRT1 activity assays, overexpression rescue, and BRD4 inhibitor treatment in cells and ethanol-fed mice","pmids":["40959274"],"confidence":"Medium","gaps":["Single lab study","Direct contribution of restored ER-phagy versus other effects to neuroprotection not dissected","Generality beyond ethanol context untested"]},{"year":null,"claim":"How the protein's cancer-associated activities (calcium modulation, MMP-2/CD44, invasion) and its mitotic role mechanistically relate to its ER-phagy receptor function remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experiment connects ER-phagy activity to the cancer readouts","Mechanism of intracellular calcium modulation undefined","No structural or biochemical model of substrate selection"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,4,8]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NC44","full_name":"Reticulophagy regulator 2","aliases":[],"length_aa":543,"mass_kda":57.8,"function":"Endoplasmic reticulum (ER)-anchored autophagy regulator which exists in an inactive state under basal conditions but is activated following cellular stress (PubMed:34338405). When activated, induces ER fragmentation and mediates ER delivery into lysosomes through sequestration into autophagosomes via interaction with ATG8 family proteins (PubMed:34338405). Required for collagen quality control in a LIR motif-independent manner (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q8NC44/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RETREG2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARL6IP1","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RETREG2","total_profiled":1310},"omim":[{"mim_id":"621479","title":"MICRO RNA 940; MIR940","url":"https://www.omim.org/entry/621479"},{"mim_id":"621473","title":"RETICULOPHAGY REGULATOR FAMILY, MEMBER 2; RETREG2","url":"https://www.omim.org/entry/621473"},{"mim_id":"616498","title":"RETICULOPHAGY REGULATOR FAMILY, MEMBER 3; RETREG3","url":"https://www.omim.org/entry/616498"},{"mim_id":"613114","title":"RETICULOPHAGY REGULATOR 1; RETREG1","url":"https://www.omim.org/entry/613114"},{"mim_id":"602732","title":"RHO GTPase-ACTIVATING PROTEIN 1; ARHGAP1","url":"https://www.omim.org/entry/602732"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RETREG2"},"hgnc":{"alias_symbol":["MGC3035","MAG-2"],"prev_symbol":["C2orf17","FAM134A"]},"alphafold":{"accession":"Q8NC44","domains":[{"cath_id":"-","chopping":"32-125_153-168","consensus_level":"medium","plddt":77.5195,"start":32,"end":168},{"cath_id":"1.20.5","chopping":"228-262","consensus_level":"medium","plddt":76.6391,"start":228,"end":262}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NC44","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NC44-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NC44-F1-predicted_aligned_error_v6.png","plddt_mean":58.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RETREG2","jax_strain_url":"https://www.jax.org/strain/search?query=RETREG2"},"sequence":{"accession":"Q8NC44","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NC44.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NC44/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NC44"}},"corpus_meta":[{"pmid":"16595502","id":"PMC_16595502","title":"Tumor targeting by an aptamer.","date":"2006","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16595502","citation_count":294,"is_preprint":false},{"pmid":"29440427","id":"PMC_29440427","title":"Cancer-secreted hsa-miR-940 induces an osteoblastic phenotype in the bone metastatic microenvironment via targeting ARHGAP1 and FAM134A.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29440427","citation_count":210,"is_preprint":false},{"pmid":"34338405","id":"PMC_34338405","title":"Role of FAM134 paralogues in endoplasmic reticulum remodeling, ER-phagy, and Collagen quality control.","date":"2021","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/34338405","citation_count":97,"is_preprint":false},{"pmid":"17964117","id":"PMC_17964117","title":"Expression of oligodendrocyte-associated genes in dorsolateral prefrontal cortex of patients with schizophrenia.","date":"2007","source":"Schizophrenia research","url":"https://pubmed.ncbi.nlm.nih.gov/17964117","citation_count":90,"is_preprint":false},{"pmid":"7928088","id":"PMC_7928088","title":"Activity of two synthetic amphiphilic peptides and magainin-2 against herpes simplex virus types 1 and 2.","date":"1994","source":"International journal of peptide and protein research","url":"https://pubmed.ncbi.nlm.nih.gov/7928088","citation_count":54,"is_preprint":false},{"pmid":"29097687","id":"PMC_29097687","title":"Genome-scale single-cell mechanical phenotyping reveals disease-related genes involved in mitotic rounding.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29097687","citation_count":50,"is_preprint":false},{"pmid":"1753106","id":"PMC_1753106","title":"Identification and characterization of a new gene family induced during macrophage activation.","date":"1991","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1753106","citation_count":47,"is_preprint":false},{"pmid":"2423646","id":"PMC_2423646","title":"Jimpy mice: quantitation of myelin-associated glycoprotein and other proteins.","date":"1986","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2423646","citation_count":47,"is_preprint":false},{"pmid":"12396730","id":"PMC_12396730","title":"Murine GBP-5, a new member of the murine guanylate-binding protein family, is coordinately regulated with other GBPs in vivo and in vitro.","date":"2002","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/12396730","citation_count":46,"is_preprint":false},{"pmid":"7506345","id":"PMC_7506345","title":"Phylogenetic relationships of reverse transcriptase and RNase H sequences and aspects of genome structure in the gypsy group of retrotransposons.","date":"1993","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/7506345","citation_count":46,"is_preprint":false},{"pmid":"7679782","id":"PMC_7679782","title":"The T-lymphocyte response against myelin-associated glycoprotein and myelin basic protein in patients with multiple sclerosis.","date":"1993","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/7679782","citation_count":40,"is_preprint":false},{"pmid":"19484236","id":"PMC_19484236","title":"99mTcO(MAG2-3G3-dimer): a new integrin alpha(v)beta(3)-targeted SPECT radiotracer with high tumor uptake and favorable pharmacokinetics.","date":"2009","source":"European journal of nuclear medicine and molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/19484236","citation_count":37,"is_preprint":false},{"pmid":"627402","id":"PMC_627402","title":"Lysosomal phospholipids from rat liver after treatment with different drugs.","date":"1978","source":"Hoppe-Seyler's Zeitschrift fur physiologische Chemie","url":"https://pubmed.ncbi.nlm.nih.gov/627402","citation_count":37,"is_preprint":false},{"pmid":"2454299","id":"PMC_2454299","title":"Comparative immunocytochemistry of Pelizaeus-Merzbacher disease, the jimpy mouse, and the myelin-deficient rat.","date":"1988","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/2454299","citation_count":34,"is_preprint":false},{"pmid":"9370205","id":"PMC_9370205","title":"Sex differences in function of a pheromonally stimulated pathway: role of steroids and the main olfactory system.","date":"1997","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/9370205","citation_count":32,"is_preprint":false},{"pmid":"36044577","id":"PMC_36044577","title":"Phosphorylation of FAM134C by CK2 controls starvation-induced ER-phagy.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36044577","citation_count":30,"is_preprint":false},{"pmid":"17846143","id":"PMC_17846143","title":"Global phenotype screening and transcript analysis outlines the inhibitory mode(s) of action of two amphibian-derived, alpha-helical, cationic peptides on Saccharomyces cerevisiae.","date":"2007","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/17846143","citation_count":27,"is_preprint":false},{"pmid":"23199569","id":"PMC_23199569","title":"Evaluation of 188Re-MAG2-RGD-bombesin for potential prostate cancer therapy.","date":"2012","source":"Nuclear medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/23199569","citation_count":16,"is_preprint":false},{"pmid":"37268908","id":"PMC_37268908","title":"A homozygous missense mutation in the fibroblast growth factor 5 gene is associated with the long-hair trait in Angora rabbits.","date":"2023","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37268908","citation_count":14,"is_preprint":false},{"pmid":"33504897","id":"PMC_33504897","title":"Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33504897","citation_count":13,"is_preprint":false},{"pmid":"36464103","id":"PMC_36464103","title":"Osteoclast-derived extracellular miR-106a-5p promotes osteogenic differentiation and facilitates bone defect healing.","date":"2022","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/36464103","citation_count":12,"is_preprint":false},{"pmid":"34854256","id":"PMC_34854256","title":"The crystal structure of the FAM134B-GABARAP complex provides mechanistic insights into the selective binding of FAM134 to the GABARAP subfamily.","date":"2021","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/34854256","citation_count":10,"is_preprint":false},{"pmid":"36324521","id":"PMC_36324521","title":"The antimicrobial peptide Magainin-2 interacts with BamA impairing folding of E. coli membrane proteins.","date":"2022","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36324521","citation_count":10,"is_preprint":false},{"pmid":"29488637","id":"PMC_29488637","title":"Human Liver Fatty Acid Binding Protein-1 T94A Variant, Nonalcohol Fatty Liver Disease, and Hepatic Endocannabinoid System.","date":"2018","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/29488637","citation_count":10,"is_preprint":false},{"pmid":"19212629","id":"PMC_19212629","title":"MAG-2 promotes invasion, mobility and adherence capability of lung cancer cells by MMP-2, CD44 and intracellular calcium in vitro.","date":"2009","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19212629","citation_count":9,"is_preprint":false},{"pmid":"33544106","id":"PMC_33544106","title":"Ag/AgCl@MIL-88A(Fe) heterojunction ternary composites: towards the photocatalytic degradation of organic pollutants.","date":"2021","source":"Dalton transactions (Cambridge, England : 2003)","url":"https://pubmed.ncbi.nlm.nih.gov/33544106","citation_count":9,"is_preprint":false},{"pmid":"39039299","id":"PMC_39039299","title":"Fam134c and Fam134b shape axonal endoplasmic reticulum architecture in vivo.","date":"2024","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/39039299","citation_count":7,"is_preprint":false},{"pmid":"31137349","id":"PMC_31137349","title":"Inactivation of Food-borne Pathogens with Magainin Peptides a.","date":"1995","source":"Journal of food protection","url":"https://pubmed.ncbi.nlm.nih.gov/31137349","citation_count":7,"is_preprint":false},{"pmid":"23287502","id":"PMC_23287502","title":"Acyl migration evaluation in monoacylglycerols from Echium plantagineum seed oil and Marinol.","date":"2013","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/23287502","citation_count":6,"is_preprint":false},{"pmid":"38557779","id":"PMC_38557779","title":"Variants in autophagy genes MTMR12 and FAM134A are putative modifiers of the hepatic phenotype in α1-antitrypsin deficiency.","date":"2024","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/38557779","citation_count":5,"is_preprint":false},{"pmid":"35266554","id":"PMC_35266554","title":"2-Arachidonoyl glycerol suppresses gastric emptying via the cannabinoid receptor 1-cholecystokinin signaling pathway in mice.","date":"2022","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/35266554","citation_count":5,"is_preprint":false},{"pmid":"39804497","id":"PMC_39804497","title":"A comprehensive pan-cancer analysis of RNF187 in human tumors.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39804497","citation_count":5,"is_preprint":false},{"pmid":"34533218","id":"PMC_34533218","title":"2-Arachidonoyl glycerol potently induces cholecystokinin secretion in murine enteroendocrine STC-1 cells via cannabinoid receptor CB1.","date":"2021","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/34533218","citation_count":5,"is_preprint":false},{"pmid":"38211536","id":"PMC_38211536","title":"Andean soil-derived lignocellulolytic bacterial consortium as a source of novel taxa and putative plastic-active enzymes.","date":"2023","source":"Systematic and applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38211536","citation_count":4,"is_preprint":false},{"pmid":"1708339","id":"PMC_1708339","title":"A human monoclonal IgG reactive with a private idiotope of a monoclonal IgM with autoantibody activity against myelin-associated glycoprotein.","date":"1991","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1708339","citation_count":4,"is_preprint":false},{"pmid":"8821484","id":"PMC_8821484","title":"mRNA levels for central nervous system myelin proteins in myelin deficiency of caprine beta-mannosidosis.","date":"1996","source":"Brain research. Developmental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/8821484","citation_count":3,"is_preprint":false},{"pmid":"36680491","id":"PMC_36680491","title":"Peptide grafting on intraosseous transcutaneous amputation prostheses to promote sealing with skin cells: Potential to limit infections.","date":"2023","source":"Journal of biomedical materials research. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36680491","citation_count":1,"is_preprint":false},{"pmid":"21310131","id":"PMC_21310131","title":"[Identification of novel metastasis associated genes MAG-1 and MAG-2].","date":"2003","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21310131","citation_count":0,"is_preprint":false},{"pmid":"20735960","id":"PMC_20735960","title":"[The proliferation promoting effects of MAG-2 on human lung cancer cell PLA801.].","date":"2008","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20735960","citation_count":0,"is_preprint":false},{"pmid":"40959274","id":"PMC_40959274","title":"Recovery of FAM134A-mediated ER-phagy through BRD4 inhibition alleviates ethanol-induced neurodegeneration.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40959274","citation_count":0,"is_preprint":false},{"pmid":"41593210","id":"PMC_41593210","title":"ER-phagy receptors: structural mechanisms in selective ER degradation and disease implications.","date":"2026","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/41593210","citation_count":0,"is_preprint":false},{"pmid":"41233432","id":"PMC_41233432","title":"Structure of a barrel-stave pore formed by magainin-2 reveals anion selectivity and zipper-mediated assembly.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41233432","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22886,"output_tokens":3120,"usd":0.057729,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10054,"output_tokens":2728,"usd":0.059235,"stage2_stop_reason":"end_turn"},"total_usd":0.116964,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about RETREG2 (also known as FAM134A, C2orf17, MGC3035, MAG-2 in the context of this gene). \n\nLet me classify each paper:\n- Papers about FAM134A/RETREG2 (the ER-phagy receptor): [2], [3], [6], [16], [22], [25], [27], [30], [38], [39], [40], [41]\n- Papers about MAG-2 as macrophage activation gene (a different protein): [7], [9] — these are about murine GBP family/macrophage genes, NOT FAM134A\n- Papers about myelin-associated glycoprotein (MAG): [4], [8], [11], [14], [36] — different protein\n- Papers about Magainin-2 peptide (Mag-2): [1], [5], [12], [13], [17], [18], [23], [28], [29], [31], [33], [37], [42] — different entity\n- Papers [19], [21] mention FAM134A as miRNA target but establish something about the gene\n- Papers [20], [32] are expression/correlation studies\n- Papers [10], [15], [24], [26], [34], [35] — irrelevant collisions\n\nNow extracting mechanistic discoveries:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM134A (RETREG2) functions as an ER-phagy receptor that, upon autophagy induction or ER stress, induces ER fragmentation and subsequent lysosomal degradation. FAM134A maintains ER morphology in a LC3-interacting region (LIR)-dependent manner. Notably, FAM134A can act in a LIR-independent manner to compensate for loss of FAM134B and FAM134C in degrading pro-Collagen I as a shared ER-phagy substrate, whereas FAM134C cannot compensate for loss of its paralogues.\",\n      \"method\": \"Overexpression and knockout cell lines with global proteomic analysis, ER-phagy flux assays, LIR-mutant constructs, collagen I substrate degradation assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO lines, OE, proteomics, LIR mutagenesis, substrate assays) in a single rigorous study with functional validation\",\n      \"pmids\": [\"34338405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FAM134A (RETREG2) is localized to the endoplasmic reticulum, and its depletion by RNAi impairs mitotic progression by affecting metaphase plate alignment and intracellular pressure generation, the latter through delocalization of cortical myosin II.\",\n      \"method\": \"Genome-scale RNAi screen with microcantilever-based single-cell mechanical phenotyping; protein localization by fluorescence microscopy; measurement of mitotic rounding force, pressure, and volume\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-scale RNAi screen with quantitative mechanical readouts and localization data, single study with two orthogonal methods but no rescue or mutagenesis\",\n      \"pmids\": [\"29097687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM134B (the closest paralogue) preferentially binds the GABARAP subfamily of Atg8 proteins over the LC3 subfamily via its LIR motif plus a C-terminal helix, and structural analysis suggests these binding properties are conserved in FAM134A.\",\n      \"method\": \"Crystal structure of FAM134B-GABARAP complex; binding affinity measurements; inference extended to FAM134A by sequence/structural conservation analysis\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — structural and binding data are for FAM134B; FAM134A conservation is inferred, not directly tested\",\n      \"pmids\": [\"34854256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FAM134C (a paralogue) is phosphorylated by casein kinase 2 (CK2) at residues flanking its LIR domain under fed conditions, reducing LC3-binding affinity and suppressing ER-phagy; mTORC1 inhibition during starvation limits CK2-mediated phosphorylation, thereby activating FAM134C-dependent ER-phagy. This phosphorylation-based activation mechanism is specific to FAM134C and not described for FAM134A.\",\n      \"method\": \"Phospho-mutagenesis, CK2 kinase assays, LC3 binding affinity measurements, FAM134C knockout mice, in vivo ER-phagy reporter\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous mechanistic study but pertains directly to FAM134C paralogue; FAM134A is mentioned only for structural comparison and is not directly tested\",\n      \"pmids\": [\"36044577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM134A (RETREG2) variants can accelerate degradation of misfolded α1-antitrypsin variant Z in iPSC-derived hepatocyte-like cells, while a specific FAM134A variant combined with an MTMR12 variant slows this degradation, implicating FAM134A-mediated ER-phagy as a modifier of hepatic proteotoxicity in α1-antitrypsin deficiency.\",\n      \"method\": \"Genomic sequencing of patient families; iPSC-derived hepatocyte-like cell assays measuring α1-antitrypsin variant Z degradation kinetics with patient-specific variants\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional testing of FAM134A variants in disease-relevant human cells with quantitative substrate degradation readout, single study\",\n      \"pmids\": [\"38557779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAG-2 (identified as FAM134A/RETREG2 in the lung cancer context) promotes invasion, mobility, and adherence of lung cancer cells, with overexpression upregulating MMP-2 and CD44 expression and increasing intracellular free calcium ion concentration, while knockdown reduces these metastatic properties.\",\n      \"method\": \"Gene transfection (overexpression) and RNAi (knockdown) in lung cancer cells; invasion/migration assays; RT-PCR and Western blot for MMP-2 and CD44; Fluo-3-AM calcium imaging\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — bidirectional gain/loss-of-function with multiple molecular readouts in a single lab; no independent replication\",\n      \"pmids\": [\"19212629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MAG-2 (FAM134A/RETREG2) promotes lung cancer cell proliferation by increasing PCNA mRNA levels, downregulating p53 protein, and elevating intracellular cytoplasmic free calcium concentration; knockdown decreases calcium levels and restrains proliferation.\",\n      \"method\": \"Stable transfection of sense/antisense MAG-2 vectors in PLA801 cells; MTT proliferation assay; RT-PCR for PCNA; Western blot for p53; Fluo-3-AM calcium staining; cell cycle analysis\",\n      \"journal\": \"Zhongguo fei ai za zhi = Chinese journal of lung cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single study, multiple readouts but in a non-peer-reviewed Chinese journal with limited replication\",\n      \"pmids\": [\"20735960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM134A and FAM134B are dispensable individually, but combined deletion of FAM134B and FAM134C (not FAM134A) in mice causes rapid neuromuscular degeneration and death, with loss of motor and sensory axons and expanded tubular ER with ladder-like appearance in long axons; FAM134A cannot compensate for combined FAM134B/FAM134C loss in axonal ER architecture.\",\n      \"method\": \"Single and combined knockout mice; neuromuscular phenotyping; electron microscopy of axonal ER morphology; histology of peripheral nervous system\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis with multiple KO combinations and ultrastructural readout; FAM134A's inability to compensate is a direct genetic finding, single study\",\n      \"pmids\": [\"39039299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ethanol reduces FAM134A expression in neuronal cells and mouse hippocampus through an epigenetic mechanism: ethanol metabolism suppresses SIRT1 activity, leading to increased H4K16 acetylation, enhanced BRD4 recruitment to the FAM134A promoter, and BRD4/G9a complex-mediated H3K9 dimethylation that blocks XBP1s-dependent transcription of FAM134A. BRD4 inhibition or FAM134A overexpression restores ER-phagy and prevents synaptic loss and neuronal death.\",\n      \"method\": \"ChIP assays for histone marks and BRD4/G9a at FAM134A promoter; SIRT1 activity assays; FAM134A overexpression rescue; BRD4 inhibitor treatment in cells and ethanol-fed mice; cognitive function testing\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal epigenetic and functional methods in vitro and in vivo, single lab study\",\n      \"pmids\": [\"40959274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"MAG-2 (subsequently identified as FAM134A/RETREG2) was identified as a gene with a 9-exon, 5.2 kb structure located on chromosome 2q35, showing higher expression in high-metastatic versus low-metastatic lung cancer cell sublines derived from the same parental line.\",\n      \"method\": \"Suppression subtractive hybridization (SSH) library construction and gene chip screening; sequencing and GenBank analysis; ORF and structural prediction\",\n      \"journal\": \"Zhongguo fei ai za zhi = Chinese journal of lung cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — initial identification by differential expression/sequencing with no direct functional experiment\",\n      \"pmids\": [\"21310131\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RETREG2/FAM134A is an ER-resident protein that functions as an ER-phagy receptor, promoting ER fragmentation and lysosomal degradation upon autophagy induction or ER stress through its LIR motif; it can also act LIR-independently to degrade substrates such as pro-Collagen I and compensate for loss of FAM134B/FAM134C, though it cannot substitute for the combined FAM134B/FAM134C function in maintaining axonal tubular ER architecture in vivo; its expression is regulated epigenetically by a BRD4/G9a axis downstream of SIRT1, and in cancer cell contexts it has been shown to modulate intracellular calcium, MMP-2, CD44, and cell proliferation/invasion, though the mechanistic links between these cancer-related functions and its ER-phagy receptor role remain to be fully resolved.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RETREG2 (FAM134A) is an endoplasmic reticulum-resident ER-phagy receptor that drives ER fragmentation and lysosomal degradation of ER membrane upon autophagy induction or ER stress [#0]. It maintains ER morphology through its LC3-interacting region (LIR), but can also act LIR-independently to compensate for loss of its paralogues FAM134B and FAM134C in degrading the shared ER-phagy substrate pro-Collagen I [#0]. This receptor activity has disease relevance: RETREG2 variants modulate ER-phagy-mediated clearance of the misfolded α1-antitrypsin variant Z in iPSC-derived hepatocytes, positioning RETREG2 as a modifier of hepatic proteotoxicity in α1-antitrypsin deficiency [#4]. RETREG2 expression is controlled epigenetically through a SIRT1–BRD4/G9a axis that regulates XBP1s-dependent transcription, and its loss compromises ER-phagy and promotes neuronal death, while its restoration is protective [#8]. Beyond its canonical ER-phagy role, RETREG2 was independently characterized in lung cancer (as MAG-2) where it promotes proliferation and invasion in association with elevated intracellular calcium, MMP-2, and CD44 [#5, #6], and is required for normal mitotic progression and intracellular pressure generation [#1]; how these activities connect to its ER-phagy receptor function is not resolved in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the existence and genomic structure of the gene (then MAG-2) and its first functional association — differential expression correlating with metastatic potential — before any molecular role was known.\",\n      \"evidence\": \"Suppression subtractive hybridization and gene chip screening of metastatic lung cancer cell sublines\",\n      \"pmids\": [\"21310131\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct functional experiment\", \"Correlative expression only, no causal mechanism\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Tested whether the gene actively drives a cancer phenotype, showing gain/loss of function alters proliferation alongside changes in PCNA, p53, and intracellular calcium.\",\n      \"evidence\": \"Sense/antisense stable transfection in PLA801 lung cancer cells with proliferation, RT-PCR, Western, and calcium imaging readouts\",\n      \"pmids\": [\"20735960\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single lab, non-peer-reviewed journal\", \"Mechanism linking calcium to proliferation not defined\", \"No connection yet to ER biology\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended the cancer phenotype to invasion/metastasis, linking the gene to MMP-2, CD44, and intracellular calcium through bidirectional perturbation.\",\n      \"evidence\": \"Overexpression and RNAi in lung cancer cells with invasion/migration assays and molecular readouts\",\n      \"pmids\": [\"19212629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No independent replication\", \"Mechanistic link between the gene and MMP-2/CD44 induction unresolved\", \"Relationship to later-defined ER-phagy role unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localized the protein to the ER and revealed a role in cell division, where depletion impairs metaphase plate alignment and intracellular pressure via cortical myosin II delocalization.\",\n      \"evidence\": \"Genome-scale RNAi screen with microcantilever single-cell mechanical phenotyping and fluorescence localization\",\n      \"pmids\": [\"29097687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue or mutagenesis to confirm specificity\", \"Mechanism connecting ER localization to mitotic pressure unclear\", \"Not linked to ER-phagy function\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the protein's core molecular identity as a LIR-dependent ER-phagy receptor that fragments ER for lysosomal degradation, and uniquely can substitute LIR-independently for its paralogues in degrading pro-Collagen I.\",\n      \"evidence\": \"Knockout and overexpression cell lines, global proteomics, ER-phagy flux assays, LIR mutants, and collagen I substrate degradation assays\",\n      \"pmids\": [\"34338405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of LIR-independent substrate degradation undefined\", \"Atg8-family binding preference not directly measured for this protein\", \"No structural model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated disease-relevant ER-phagy function, showing the protein's variants modify clearance of misfolded α1-antitrypsin variant Z in human hepatocytes.\",\n      \"evidence\": \"Patient family genomic sequencing and iPSC-derived hepatocyte degradation kinetics with patient-specific variants\",\n      \"pmids\": [\"38557779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Molecular basis of variant effects on receptor activity not resolved\", \"Interaction with MTMR12 variant mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the in vivo functional boundary, establishing through genetic epistasis that this protein cannot compensate for combined FAM134B/FAM134C loss in maintaining axonal tubular ER architecture.\",\n      \"evidence\": \"Single and combined knockout mice with neuromuscular phenotyping and electron microscopy of axonal ER\",\n      \"pmids\": [\"39039299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why compensation fails in axons but succeeds for collagen is unexplained\", \"Tissue-specific contribution of the protein not isolated\", \"Single study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an upstream regulatory axis controlling protein expression, showing a SIRT1–BRD4/G9a chromatin pathway gates XBP1s-dependent transcription and that restoring the protein rescues ER-phagy and neuronal survival.\",\n      \"evidence\": \"ChIP for histone marks and BRD4/G9a, SIRT1 activity assays, overexpression rescue, and BRD4 inhibitor treatment in cells and ethanol-fed mice\",\n      \"pmids\": [\"40959274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"Direct contribution of restored ER-phagy versus other effects to neuroprotection not dissected\", \"Generality beyond ethanol context untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the protein's cancer-associated activities (calcium modulation, MMP-2/CD44, invasion) and its mitotic role mechanistically relate to its ER-phagy receptor function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experiment connects ER-phagy activity to the cancer readouts\", \"Mechanism of intracellular calcium modulation undefined\", \"No structural or biochemical model of substrate selection\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 4, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}