{"gene":"RETREG1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2009,"finding":"Loss-of-function mutations in FAM134B cause hereditary sensory and autonomic neuropathy type II (HSAN II). FAM134B knockdown results in structural alterations of the cis-Golgi compartment and induces apoptosis in primary dorsal root ganglion neurons, establishing FAM134B as critical for long-term survival of nociceptive and autonomic ganglion neurons.","method":"siRNA knockdown in primary dorsal root ganglion neurons, morphological analysis of cis-Golgi, apoptosis assays; human loss-of-function mutations identified","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function human genetics combined with cellular knockdown and defined phenotypic readouts, replicated across multiple families","pmids":["19838196"],"is_preprint":false},{"year":2017,"finding":"FAM134B is an ER-localized reticulophagy receptor that acts as a host restriction factor for dengue virus (DENV) and Zika virus (ZIKV). The flavivirus NS3 protease directly cleaves FAM134B at a single site within its reticulon homology domain (RHD), blocking ER/viral protein-enriched autophagosome formation and suppressing the reticulophagy pathway to promote viral replication.","method":"RNAi depletion, viral replication assays, in vitro protease cleavage assay identifying the cleavage site within the RHD, autophagosome formation quantification","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct in vitro cleavage assay combined with RNAi phenotype and autophagosome quantification, multiple viruses tested","pmids":["28102736"],"is_preprint":false},{"year":2018,"finding":"The ER-resident lectin chaperone Calnexin (CANX) acts as a co-receptor that recognizes ER-luminal misfolded procollagens and physically interacts with the ER-phagy receptor FAM134B. FAM134B in turn binds autophagosome membrane-associated LC3 and delivers a portion of ER containing both CANX and misfolded procollagen to the lysosome for degradation, constituting selective ER-phagy-based quality control.","method":"siRNA/CRISPR-Cas9/knockout gene deletion, co-immunoprecipitation of CANX–FAM134B complex, LC3 binding assay, lysosomal degradation assay in collagen-producing cells","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP establishing CANX–FAM134B complex, multiple genetic tools (siRNA, CRISPR, KO), functional readout (procollagen degradation)","pmids":["30559329"],"is_preprint":false},{"year":2019,"finding":"The reticulon homology domain (RHD) of FAM134B contains two wedge-shaped transmembrane helical hairpins and two amphipathic helices that induce membrane curvature and drive membrane remodeling. FAM134B clustering amplifies membrane-shaping effects, and disruption of the RHD structure impairs selective autophagy flux and leads to disease states.","method":"Molecular dynamics simulations of RHD in flat and curved membranes, in vitro liposome remodeling assays by electron microscopy, structural modeling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro liposome remodeling validated by EM combined with MD simulation structural model and autophagy flux readouts","pmids":["31147549"],"is_preprint":false},{"year":2020,"finding":"FAM134B oligomerization through its reticulon-homology domain is required for ER membrane fragmentation in vitro and ER-phagy in vivo. Under ER-stress conditions, CAMK2B phosphorylates the RHD of FAM134B, enhancing FAM134B oligomerization and membrane fragmentation activity. The HSAN patient variant FAM134B G216R exhibits gain-of-function hyperactive self-association and membrane scission, resulting in excessive ER-phagy and sensory neuron death.","method":"In vitro membrane fragmentation assays, oligomerization assays, CAMK2B kinase assay with phosphorylation mapping, ER-phagy flux assays in vivo, analysis of patient-derived G216R variant","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of membrane fragmentation, kinase assay with mutagenesis, in vivo ER-phagy quantification, disease variant characterization","pmids":["31930741"],"is_preprint":false},{"year":2020,"finding":"The nutrient-responsive transcription factors TFEB and TFE3 directly control ER-phagy by inducing transcription of FAM134B. The TFEB/TFE3–FAM134B axis promotes ER-phagy activation upon prolonged starvation. In chondrocytes, FGF signaling activates JNK-dependent proteasomal degradation of IRS1, which inhibits PI3K–PKB/Akt–mTORC1 and promotes TFEB/TFE3 nuclear translocation to enhance FAM134B transcription.","method":"Transcription factor overexpression/knockdown, FAM134B promoter reporter assays, genetic epistasis in chondrocytes, medaka fish FAM134B knockout for in vivo validation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — transcriptional reporter assays, epistasis experiments, in vivo vertebrate model, multiple orthogonal methods","pmids":["32716134"],"is_preprint":false},{"year":2020,"finding":"RETREG1/FAM134B mediates dual organelle turnover (reticulo-mito-phagy) by interacting with OPA1 (inner mitochondrial membrane protein) when AMFR-destabilized mitochondria form 'mitoplasts' that bring the inner mitochondrial membrane into ER proximity. RETREG1-dependent autophagosomal degradation of both AMFR and OPA1 occurs simultaneously.","method":"Co-immunoprecipitation of RETREG1–OPA1 interaction, structured illumination and STED microscopy, autophagosomal degradation assays, stress induction with CCCP","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying OPA1 interaction, super-resolution microscopy, single lab with multiple imaging and biochemical methods","pmids":["32559118"],"is_preprint":false},{"year":2021,"finding":"The crystal structure of the FAM134B–GABARAP complex reveals that FAM134B binds to the GABARAP subfamily more strongly than to the LC3 subfamily. FAM134B uses both its LIR core motif and a C-terminal helix to bind GABARAP, and structural determinants for this binding selectivity were identified.","method":"Crystal structure determination of FAM134B–GABARAP complex, binding affinity measurements, mutagenesis to identify selectivity determinants","journal":"FEBS open bio","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional binding validation and mutagenesis, single lab but rigorous structural and biochemical approach","pmids":["34854256"],"is_preprint":false},{"year":2021,"finding":"FAM134B-RHD spontaneously forms clusters driven by curvature-mediated attractions. At a critical cluster size, FAM134B-RHD induces membrane bud formation. Budding kinetics depend on protein concentration and bilayer asymmetry.","method":"Molecular dynamics simulations of FAM134B-RHD clustering and membrane budding","journal":"The journal of physical chemistry letters","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — computational simulation only, no direct in vitro or in vivo experimental validation in this paper","pmids":["33591770"],"is_preprint":false},{"year":2022,"finding":"O-GlcNAc transferase (OGT) directly associates with FAM134B and O-GlcNAcylates it, which reduces FAM134B ubiquitination-mediated degradation, thereby stabilizing FAM134B and enhancing FAM134B-mediated ER-phagy under nutrient deprivation.","method":"Co-IP of OGT–FAM134B complex, O-GlcNAcylation site mapping, ubiquitination assays comparing wild-type vs. O-GlcNAc-mutant FAM134B, genetic manipulation in cells and rat IDD model","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, post-translational modification mapping, ubiquitination competition assay, in vivo rat model, single lab","pmids":["36056188"],"is_preprint":false},{"year":2022,"finding":"SARS-CoV-2 ORF3a localizes to the ER and induces RETREG1/FAM134B-dependent reticulophagy through the HMGB1–BECN1 (beclin 1) pathway, leading to ER stress and inflammatory responses that facilitate SARS-CoV-2 infection.","method":"ORF3a overexpression/localization studies, FAM134B knockdown combined with reticulophagy flux assays, HMGB1–BECN1 pathway epistasis experiments","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis, reticulophagy flux assays, localization studies, single lab","pmids":["35239449"],"is_preprint":false},{"year":2022,"finding":"GSDMD promotes autophagy and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity by forming pores on the ER membrane via its N-terminus, thereby activating FAM134B-mediated ER stress. FAM134B then interacts with autophagic protein LC3 to induce cardiac autophagy.","method":"GSDMD overexpression/knockdown in cardiomyocytes, ER membrane pore formation assay, co-IP of FAM134B–LC3, autophagy flux assays, in vivo mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of FAM134B–LC3, GSDMD N-terminus pore formation experiment, in vivo and in vitro data, single lab","pmids":["36289195"],"is_preprint":false},{"year":2023,"finding":"FAM134B is acetylated by the acetyltransferase CBP, which elicits intense ER-phagy. FAM134B acetylation subsequently promotes CAMKII-mediated phosphorylation for sustained ER-phagy. Conversely, the deacetylase SIRT7 deacetylates FAM134B to temper its ER-phagy activity and prevent excessive ER degradation.","method":"In vitro acetylation assay with CBP, deacetylation assay with SIRT7, phosphorylation assay with CAMKII, ER-phagy flux measurements, mutagenesis of acetylation sites","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assays for acetylation and deacetylation, phosphorylation cascade validation, mutagenesis, functional ER-phagy readouts, single lab but multiple orthogonal methods","pmids":["37043189"],"is_preprint":false},{"year":2023,"finding":"Coronavirus ORF8 binds FAM134B and ATL3 and undergoes condensation with p62, sequestering FAM134B and ATL3 into ORF8/p62 liquid droplets. This disrupts ER-phagy, facilitates viral double-membrane vesicle (DMV) formation, and activates ER stress.","method":"Co-IP of ORF8–FAM134B and ORF8–ATL3 interactions, phase separation/condensate assays, ER-phagy flux assays, DMV formation by EM, FAM134B knockdown/overexpression","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of viral–host protein interactions, condensate characterization, ER-phagy flux, single lab","pmids":["36952345"],"is_preprint":false},{"year":2024,"finding":"USP20 deubiquitinates FAM134B/RETREG1 by specifically cleaving K48- and K63-linked ubiquitin chains, thereby stabilizing RETREG1 and promoting reticulophagy under starvation. USP20 is recruited to the ER through its interaction with VAPs (VAMP-associated proteins), which also facilitate recruitment of WIPI2 to ER subdomains enriched in USP20 and RETREG1.","method":"DUB screen, in vitro deubiquitination assay with USP20, K48/K63 ubiquitin chain specificity assays, co-IP of USP20–VAP and USP20–RETREG1 interactions, WIPI2 recruitment assay, reticulophagy flux measurement","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro deubiquitination assay, ubiquitin linkage specificity, co-IP of multiple interactions, functional reticulophagy readout, single lab with multiple orthogonal methods","pmids":["38705724"],"is_preprint":false},{"year":2024,"finding":"TRIM21 ubiquitinates RETREG1 at K247 and K252, facilitating its proteasomal degradation. CKAP4 competitively binds RETREG1 and shields it from TRIM21-mediated degradation, thereby stabilizing RETREG1 and modulating reticulophagy. Stress-induced TRIM21 upregulation reduces RETREG1 to restore ER stress equilibrium.","method":"Co-IP of CKAP4–RETREG1 and TRIM21–RETREG1 interactions, ubiquitination site mapping (K247/K252) by mutagenesis, proteasomal degradation assays, competitive binding assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ubiquitination site mutagenesis, competitive binding assay, degradation rescue experiments, multiple co-IPs, single lab","pmids":["39689859"],"is_preprint":false},{"year":2024,"finding":"FAM134B interacts with DDX3X and prevents its proteasomal degradation by reducing K48-linked polyubiquitination and enhancing K63-linked polyubiquitination of DDX3X. DDX3X stabilization promotes transcription of Rac1, activating AKT signaling in hepatocellular carcinoma. DDX3X also reciprocally increases FAM134B transcriptional activity, forming a positive feedback loop.","method":"Co-IP of FAM134B–DDX3X, ubiquitin linkage assays (K48/K63), Rac1 transcription reporter, AKT signaling readouts, FAM134B knockdown in vivo/in vitro","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitin linkage characterization, transcriptional reporter, in vivo HCC model, single lab","pmids":["41198618"],"is_preprint":false},{"year":2024,"finding":"FAM134B interacts with the canonical mitochondrial fission-promoting protein DRP1. Functional depletion of FAM134B leads to local actin rearrangement and reduced DRP1 recruitment onto mitochondria, resulting in mitochondrial hyperfusion. FAM134B levels decrease with aging in rat brains and in Parkinson's disease models.","method":"Co-IP of FAM134B–DRP1, fluorescence microscopy of mitochondrial morphology, actin staining, DRP1 recruitment assay upon FAM134B knockdown/KO","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of FAM134B–DRP1, functional mitochondrial morphology readout, actin rearrangement assay, single lab","pmids":["41178515"],"is_preprint":false},{"year":2024,"finding":"FAM134B degrades STIM1 (an ER Ca2+ sensor) via ER-phagy. FAM134B binds STIM1 through its C-terminal cytosolic region; FAM134B knockdown increases STIM1 protein levels by reducing its transport from ER to autolysosomes, accelerates G1-to-S phase transition, and promotes cell proliferation.","method":"Co-IP of FAM134B–STIM1, ER-to-autolysosome trafficking assay, cell cycle analysis (G1/S), cell proliferation assay upon FAM134B knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying binding region, trafficking assay, cell cycle readout, single lab","pmids":["39128711"],"is_preprint":false},{"year":2025,"finding":"FAM134B directly interacts with both cholesterol and SCAP (a key regulator of cholesterol biosynthesis). When ER cholesterol is high, FAM134B and SCAP are sequestered by cholesterol-tightened interactions, halting ER-phagy, STING activation, and cholesterol synthesis. Under low cholesterol, FAM134B dissociates from SCAP, allowing SCAP to activate SREBP2 and upregulate cholesterol synthesis, while free FAM134B facilitates ER-phagy through oligomerization or aids STING trafficking.","method":"Direct cholesterol-binding assay, co-IP of FAM134B–SCAP complex, cholesterol manipulation experiments, SREBP2 activation assay, ER-phagy and STING trafficking readouts","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct lipid-binding assay, co-IP of FAM134B–SCAP, functional pathway readouts (SREBP2, STING, ER-phagy), single lab with multiple orthogonal methods","pmids":["41083602"],"is_preprint":false},{"year":2025,"finding":"ATF4 forms a heterodimer with CEBPG/C/EBPγ and binds directly to the promoter and enhancer regions of the RETREG1 gene to transcriptionally upregulate RETREG1-mediated reticulophagy in response to lipotoxic stress. RETREG1 knockout mice exhibit more severe hepatic lipotoxicity, confirming protective function.","method":"ChIP identifying ATF4 and CEBPG binding sites in RETREG1 promoter/enhancer, co-IP of ATF4–CEBPG heterodimer, RETREG1 promoter reporter assay, retreg1 KO mouse model","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP with direct binding site identification, co-IP of transcription factor heterodimer, reporter assay, KO mouse phenotype, single lab with multiple orthogonal methods","pmids":["40437698"],"is_preprint":false},{"year":2025,"finding":"Salmonella Typhimurium inhibits ER-phagy by targeting FAM134B through the bacterial effector protein SopF, preventing FAM134B oligomerization required for efficient ER-phagy. FAM134B knockout raises intracellular Salmonella numbers, while FAM134B activation reduces bacterial burden.","method":"FAM134B knockout cells/mice infected with Salmonella, bacterial burden quantification, FAM134B oligomerization assay in presence/absence of SopF, FAM134B activation experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells and mice with defined bacterial burden readout, SopF-FAM134B mechanistic link via oligomerization assay, single lab","pmids":["40133256"],"is_preprint":false},{"year":2025,"finding":"MLV glycoGag exploits RETREG1/FAM134B to downregulate SERINC5 at the ER via micro-ER-phagy through an autophagosome-independent process that bypasses ATG3, ATG5, ATG7, BECN1, LC3 lipidation, and PIK3C3. RETREG1 knockout abolishes degradation of ER-retained SERINC5.","method":"CRISPR/Cas9 knockout of RETREG1 and autophagy genes (ATG3, ATG5, ATG7, BECN1, PIK3C3), affinity-purified mass spectrometry, SERINC5 degradation assays, co-localization studies","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic CRISPR KO of autophagy pathway components, MS interactome, defined degradation assay, independently described in two papers (PMID 41066524, 40093084)","pmids":["41066524","40093084"],"is_preprint":false},{"year":2025,"finding":"During myogenesis, FAM134B1 is degraded and replaced by FAM134B2. FAM134B2, with its partial reticulon homology domain, drives ER reshaping and reticulophagy during the active differentiation phase. Knockout of both FAM134B isoforms results in aberrant proteome landscape and dilated ER structures, rescued by FAM134B2 re-expression but only partially by FAM134B1.","method":"FAM134B double-isoform knockout in myotubes, isoform-specific re-expression rescue experiments, proteomics of ER proteome, EM for ER morphology, ER-phagy flux assays during differentiation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — isoform-specific KO with rescue, proteomics, EM morphology, functional ER-phagy readouts, single lab with multiple orthogonal methods","pmids":["39762646"],"is_preprint":false},{"year":2025,"finding":"ATF6 directly transcriptionally regulates RETREG1 expression in response to LPS-induced ER stress. RETREG1-mediated reticulophagy reduces excessive ER stress via the EIF2AK3 signaling pathway and inhibits MARCH8-dependent MHC-II ubiquitination to maintain antigen presentation in dendritic cells.","method":"ATF6 knockout mice, RETREG1 promoter analysis, Cd11ccreRetreg1fl/fl conditional KO mice, MHC-II ubiquitination assay, EIF2AK3 pathway epistasis, DC function assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mice with defined immune phenotype, transcription factor promoter validation, ubiquitination mechanistic assay, single lab","pmids":["41874459"],"is_preprint":false},{"year":2025,"finding":"RETREG1-deficiency in dendritic cells activates CASP3–GSDME-dependent pyroptosis during sepsis by inhibiting autophagic degradation of the ERGIC (ER-Golgi intermediate compartment), resulting in abnormal STING1 activation. Genetic downregulation of TMED9 prevents STING1 activation and GSDME-mediated pyroptosis by disrupting ERGIC structure.","method":"Cd11ccreRetreg1fl/fl KO mice, ERGIC turnover assays, STING1 activation assays, CASP3/GSDME cleavage readouts, Tmed9 siRNA epistasis, sepsis CLP model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, epistasis with TMED9, defined STING1–GSDME pathway readouts, in vivo sepsis model, single lab","pmids":["41787734"],"is_preprint":false},{"year":2025,"finding":"FAM134B interacts with GSTK1 (glutathione S-transferase kappa 1), and silencing GSTK1 further aggravates reduction in reticulophagy and tubular injury that can be partially blocked by RETREG1 overexpression, establishing GSTK1 as a functional partner of RETREG1 in ER homeostasis.","method":"Immunoprecipitation coupled with mass spectrometry (IP-MS) identifying GSTK1, co-IP validation, GSTK1 siRNA in proximal tubule-specific Retreg1 KO mice and HK-2 cells, reticulophagy flux assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS followed by co-IP validation, genetic epistasis in vivo and in vitro, single lab","pmids":["40778749"],"is_preprint":false},{"year":2019,"finding":"FAM134B overexpression in HeLa cells is sufficient to impair ER homeostasis, accelerate ER degradation, and cause ER stress, the unfolded protein response (UPR), and ER-phagy-dependent cell death. This demonstrates that excessive FAM134B-driven ER-phagy can itself be lethal.","method":"FAM134B overexpression in HeLa cells, ER stress markers (UPR), autophagosome number/size quantification, cell death assays, autophagy inhibitor controls","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression gain-of-function with defined ER stress and cell death readouts, pharmacological inhibitor controls, single lab","pmids":["31748416"],"is_preprint":false},{"year":2019,"finding":"In hepatocellular carcinoma, FAM134B induces tumorigenesis and epithelial-to-mesenchymal transition (EMT) via the Akt signaling pathway, with subsequent glycogen synthase kinase-3β phosphorylation, β-catenin accumulation, and Snail stabilization.","method":"FAM134B gain- and loss-of-function experiments, Akt pathway activator/inhibitor pharmacological rescue, nude mouse xenograft and lung metastasis models, Western blot for pathway components","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiments with Akt activator/inhibitor, in vivo mouse models, defined pathway readouts, single lab","pmids":["30556279"],"is_preprint":false},{"year":2018,"finding":"FAM134B physically interacts with CAP1, EB1, CYPB/PPIB, and KDELR2 in colon cancer cells. Exogenous suppression of FAM134B leads to upregulation of EB1 and reduction of KDELR2 expression; elevated EB1 promotes WNT/β-catenin signaling by inactivating the tumor suppressor APC.","method":"LC-MS/MS on anti-FAM134B co-immunoprecipitate, Western blot and confocal microscopy validation of FAM134B–EB1, FAM134B–CYPB, FAM134B–KDELR2 interactions, shRNA-mediated FAM134B silencing","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP/MS with orthogonal validation of select interactions, functional pathway readout (EB1/APC/β-catenin), single lab","pmids":["29964340"],"is_preprint":false},{"year":2018,"finding":"m6A modification of FAM134B mRNA is recognized by the m6A reader protein YTHDF2, which binds FAM134B mRNA and reduces its protein level by decreasing mRNA lifetime. A non-m6A FAM134B coding sequence (FAM134B-MUT) is expressed at higher levels, promotes porcine preadipocyte adipogenic differentiation more effectively, and upregulates PPARγ and C/EBPα.","method":"m6A site mapping on FAM134B CDS, YTHDF2 RNA immunoprecipitation, wild-type vs. m6A-mutant FAM134B transfection, mRNA stability assay, adipogenic differentiation assays","journal":"IUBMB life","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA IP establishing YTHDF2–FAM134B mRNA interaction, mRNA stability comparison, functional adipogenesis readout, single lab","pmids":["30506811"],"is_preprint":false},{"year":2023,"finding":"FAM134B (wild-type and HSAN2B-linked mutants) interact with LC3/GABARAPL1 in cells, as shown by NanoBiT reporter assay. C-terminal truncated FAM134B mutants show lower protein–protein interaction with LC3 and lower ER-phagy activity. The G216R variant retains LC3/GABARAPL1 interaction to the same extent as wild-type FAM134B.","method":"NanoBiT split-luciferase protein–protein interaction reporter assay for FAM134B–LC3/GABARAPL1 interaction, GFP-tagged ER-phagy reporter flux assay, transfection into FAM134B-deficient Neuro2a cells","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NanoBiT quantitative PPI assay for multiple mutants, ER-phagy flux reporter, single lab","pmids":["37273064"],"is_preprint":false},{"year":2024,"finding":"FAM134B and FAM134C cooperate in shaping tubular ER architecture in peripheral axons. Combined Fam134b/Fam134c double knockout (but not Fam134a combinations) in mice causes rapid neuromuscular and somatosensory degeneration, loss of motor and sensory axons, and expanded tubular ER with a transverse ladder-like appearance in long axons, without obvious cortical ER abnormalities.","method":"Single and combined FAM134 protein knockout mice, neuromuscular phenotyping, transmission electron microscopy of axonal ER morphology, peripheral nerve histopathology","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — double KO genetic epistasis in mice with defined morphological ER phenotype by EM, in vivo neurodegeneration readout","pmids":["39039299"],"is_preprint":false}],"current_model":"RETREG1/FAM134B is a multi-membrane-spanning ER-phagy receptor that uses its reticulon homology domain (RHD) to induce membrane curvature and, upon oligomerization driven by CAMK2B-mediated phosphorylation and CBP-mediated acetylation (counteracted by SIRT7 deacetylation), fragments ER membranes for lysosomal degradation; its cytosolic LIR motif binds preferentially to the GABARAP subfamily of autophagosomal proteins; it is stabilized by USP20-mediated deubiquitination (removing K48/K63 chains) and O-GlcNAcylation, and is targeted for proteasomal degradation by TRIM21 (K247/K252 ubiquitination) unless protected by CKAP4 binding; it acts in selective ER quality control through a Calnexin co-receptor complex that recognizes misfolded luminal clients (e.g., procollagen), and degrades STIM1 to regulate Ca2+-dependent cell cycle progression; FAM134B–SCAP interactions sense ER cholesterol to couple ER-phagy with SREBP2-driven cholesterol biosynthesis and STING innate immune trafficking; FAM134B also regulates mitochondrial morphology by retaining DRP1 on mitochondria; its RHD is cleaved by flavivirus NS3 proteases and hijacked by bacterial SopF (Salmonella), viral ORF8/p62 condensates (coronaviruses), and retroviral glycoGag (micro-ER-phagy) to subvert ER-phagy; loss-of-function mutations cause hereditary sensory and autonomic neuropathy type IIB (HSAN IIB) due to failure of ER homeostasis in long nociceptive and autonomic neurons, while gain-of-function hyperactive oligomerization (G216R variant) causes excessive ER-phagy and neuronal death."},"narrative":{"mechanistic_narrative":"RETREG1 (FAM134B) is an ER-resident selective autophagy receptor that drives reticulophagy — the targeted lysosomal degradation of endoplasmic reticulum — and is essential for the long-term survival of nociceptive and autonomic neurons, with loss-of-function mutations causing hereditary sensory and autonomic neuropathy [PMID:19838196, PMID:30559329]. Its reticulon homology domain (RHD) forms wedge-shaped transmembrane hairpins and amphipathic helices that induce membrane curvature, and upon clustering it amplifies membrane remodeling to fragment ER for capture by autophagosomes [PMID:31147549, PMID:31930741]. A cytosolic LIR motif together with a C-terminal helix mediates binding to the autophagosomal ATG8 proteins, with selectivity for the GABARAP subfamily over LC3 [PMID:34854256, PMID:37273064]. ER-phagy activity is gated by a dense post-translational and transcriptional control network: CAMK2B phosphorylation and CBP acetylation promote oligomerization and membrane scission, SIRT7 deacetylation tempers it, O-GlcNAcylation and USP20-mediated removal of K48/K63 ubiquitin chains stabilize the receptor, and TRIM21 ubiquitination at K247/K252 drives proteasomal turnover unless CKAP4 binding shields it [PMID:31930741, PMID:37043189, PMID:36056188, PMID:38705724, PMID:39689859]; nutrient- and stress-responsive transcription factors TFEB/TFE3, ATF4–CEBPG, ATF6, and others induce RETREG1 expression [PMID:32716134, PMID:40437698, PMID:41874459]. Functionally, RETREG1 executes selective ER quality control via a Calnexin co-receptor complex that delivers misfolded luminal procollagen for degradation, and degrades the ER Ca2+ sensor STIM1 to restrain G1-to-S cell cycle progression [PMID:30559329, PMID:39128711]. Through direct cholesterol and SCAP binding it couples ER-phagy to SREBP2-driven cholesterol synthesis and STING trafficking [PMID:41083602], and it also influences mitochondrial morphology by promoting DRP1 recruitment for fission [PMID:41178515]. RETREG1 is exploited or restricted at host–pathogen interfaces: flavivirus NS3 protease cleaves its RHD, Salmonella SopF blocks its oligomerization, coronavirus ORF8/p62 condensates sequester it, and retroviral glycoGag hijacks it for autophagosome-independent micro-ER-phagy of SERINC5 [PMID:28102736, PMID:40133256, PMID:36952345, PMID:41066524, PMID:40093084].","teleology":[{"year":2009,"claim":"Established RETREG1/FAM134B as a disease gene and as essential for neuronal survival, before any molecular function was known.","evidence":"Human loss-of-function mutations and siRNA knockdown in primary dorsal root ganglion neurons with Golgi morphology and apoptosis readouts","pmids":["19838196"],"confidence":"High","gaps":["No molecular mechanism for the survival defect","Golgi phenotype precedes identification of an ER-phagy role"]},{"year":2017,"claim":"Identified RETREG1 as an ER-phagy receptor and a flavivirus restriction factor by showing NS3 protease cleaves its reticulon homology domain to disable the pathway.","evidence":"RNAi viral replication assays and in vitro protease cleavage assay mapping a single RHD cleavage site","pmids":["28102736"],"confidence":"High","gaps":["Did not resolve how the RHD remodels membranes","Cargo selectivity not defined"]},{"year":2018,"claim":"Defined selective ER quality control by showing Calnexin acts as a luminal co-receptor delivering misfolded procollagen to the lysosome through RETREG1–LC3 coupling.","evidence":"Reciprocal co-IP of CANX–FAM134B, LC3 binding and lysosomal procollagen degradation assays with siRNA/CRISPR/KO tools","pmids":["30559329"],"confidence":"High","gaps":["How luminal misfolding signals across the membrane to the cytosolic receptor unresolved","Generality beyond procollagen clients untested"]},{"year":2019,"claim":"Provided the structural basis for membrane fragmentation, showing the RHD's transmembrane hairpins and amphipathic helices induce curvature amplified by clustering.","evidence":"Molecular dynamics simulations plus in vitro liposome remodeling validated by electron microscopy","pmids":["31147549","33591770"],"confidence":"High","gaps":["Atomic-resolution structure of the full RHD not determined","Coupling of clustering to autophagosome capture in vivo not directly shown"]},{"year":2020,"claim":"Showed oligomerization is the key activating step and is regulated by CAMK2B phosphorylation, and that a hyperactive patient variant (G216R) drives excessive ER-phagy and neuron death — establishing gain-of-function pathology distinct from loss-of-function disease.","evidence":"In vitro membrane fragmentation and oligomerization assays, CAMK2B kinase assay with phospho-mapping, in vivo ER-phagy flux, G216R variant analysis","pmids":["31930741"],"confidence":"High","gaps":["Upstream trigger of CAMK2B activation at the ER unclear","How G216R alters self-association at the structural level not resolved"]},{"year":2020,"claim":"Connected RETREG1 to nutrient-responsive transcriptional control via the TFEB/TFE3 axis downstream of mTORC1.","evidence":"Promoter reporter assays, transcription factor manipulation, chondrocyte epistasis, medaka FAM134B knockout","pmids":["32716134"],"confidence":"High","gaps":["Whether TFEB/TFE3 induction occurs in neurons unaddressed"]},{"year":2021,"claim":"Resolved ATG8 selectivity, showing RETREG1 binds the GABARAP subfamily more strongly than LC3 using both LIR core and a C-terminal helix.","evidence":"Crystal structure of FAM134B–GABARAP complex with affinity measurements and selectivity mutagenesis","pmids":["34854256","37273064"],"confidence":"High","gaps":["Functional consequence of GABARAP preference for cargo-specific ER-phagy not established"]},{"year":2023,"claim":"Expanded the activation code, showing CBP acetylation primes intense ER-phagy and licenses CAMKII phosphorylation, while SIRT7 deacetylation restrains over-degradation.","evidence":"In vitro acetylation/deacetylation/phosphorylation assays with site mutagenesis and ER-phagy flux readouts","pmids":["37043189"],"confidence":"High","gaps":["Stimuli controlling the CBP/SIRT7 balance in vivo unknown"]},{"year":2024,"claim":"Established opposing ubiquitin-based stability control: USP20 (via VAP recruitment) deubiquitinates and stabilizes the receptor, whereas TRIM21 ubiquitinates K247/K252 for degradation unless CKAP4 competitively protects it.","evidence":"In vitro deubiquitination with K48/K63 specificity, DUB screen, co-IPs, WIPI2 recruitment, ubiquitination site mutagenesis and competitive binding/degradation rescue","pmids":["38705724","39689859"],"confidence":"High","gaps":["How USP20 and TRIM21 activities are balanced under a given stress unresolved","O-GlcNAcylation stabilization mechanism (36056188) is Medium-confidence"]},{"year":2024,"claim":"Broadened the substrate repertoire and organelle reach: RETREG1 degrades STIM1 to gate the cell cycle and influences mitochondrial fission via DRP1 recruitment.","evidence":"Co-IPs (STIM1, DRP1, OPA1), ER-to-autolysosome trafficking, cell cycle analysis, mitochondrial morphology imaging","pmids":["39128711","41178515","32559118"],"confidence":"Medium","gaps":["DRP1 and OPA1 links rest on single-lab co-IP plus imaging","Direct vs. indirect effect on mitochondrial fission not disentangled"]},{"year":2025,"claim":"Identified RETREG1 as a cholesterol/SCAP sensor that couples ER-phagy to sterol biosynthesis and STING trafficking, integrating lipid metabolism with ER turnover.","evidence":"Direct cholesterol-binding assay, FAM134B–SCAP co-IP, cholesterol manipulation, SREBP2 and STING readouts","pmids":["41083602"],"confidence":"High","gaps":["Structural basis of cholesterol/SCAP sensing unresolved","Physiological tissue context of sterol coupling untested"]},{"year":2025,"claim":"Defined RETREG1 as a broadly targeted node in host–pathogen conflict, hijacked by bacteria and viruses through distinct anti-oligomerization, sequestration, and micro-ER-phagy mechanisms.","evidence":"FAM134B KO cells/mice with bacterial burden and SopF oligomerization assays, ORF8/p62 condensate assays, CRISPR KO of autophagy genes with SERINC5 degradation and interactome MS","pmids":["40133256","36952345","41066524","40093084","35239449"],"confidence":"High","gaps":["Whether autophagosome-independent micro-ER-phagy operates outside glycoGag context unknown","Shared structural determinant exploited by diverse pathogens not defined"]},{"year":2025,"claim":"Extended transcriptional and physiological control through ER-stress factors (ATF4–CEBPG, ATF6) and immune/tissue functions, including dendritic cell antigen presentation, sepsis pyroptosis, and protection from hepatic lipotoxicity.","evidence":"ChIP/promoter reporter assays, conditional and global KO mouse models, ERGIC turnover and STING1/GSDME readouts","pmids":["40437698","41874459","41787734"],"confidence":"Medium","gaps":["Tissue-specific transcriptional logic across stressors not unified","Several immune phenotypes from single-lab conditional KOs"]},{"year":2025,"claim":"Demonstrated isoform specialization, showing FAM134B2 replaces FAM134B1 during myogenesis to drive ER reshaping, and that FAM134B/FAM134C cooperate to maintain axonal tubular ER.","evidence":"Isoform-specific double KO with rescue, proteomics and EM in myotubes; combined FAM134b/c KO mouse neurodegeneration with EM of axonal ER","pmids":["39762646","39039299"],"confidence":"High","gaps":["Functional non-equivalence of paralogs mechanistically unexplained","Why neurons are uniquely vulnerable not fully resolved"]},{"year":null,"claim":"How the multiple regulatory layers — phosphorylation, acetylation, ubiquitination, O-GlcNAcylation, lipid sensing, and transcription — are integrated to set RETREG1 activity in a given cell type and stress, and how this dictates the loss- vs. gain-of-function disease balance, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking the regulatory inputs","Cell-type-specific thresholds for protective vs. lethal ER-phagy undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,4,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,7,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[19]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[17]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,2,3,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,7,18]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6,17]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2,4,14,22]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to 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Promotes membrane remodeling and ER scission via its membrane bending capacity and targets the fragments into autophagosomes via interaction with ATG8 family proteins (PubMed:26040720, PubMed:31930741, PubMed:34338405). Active under basal conditions (PubMed:34338405). Required for collagen quality control in a LIR motif-dependent manner (By similarity). Required for long-term survival of nociceptive and autonomic ganglion neurons (PubMed:19838196, PubMed:26040720) (Microbial infection) During SARS-CoV-2 infection, RETREG1-mediated reticulophagy is promoted by SARS-CoV-2 ORF3A protein (PubMed:35239449). 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type II (HSAN II). FAM134B knockdown results in structural alterations of the cis-Golgi compartment and induces apoptosis in primary dorsal root ganglion neurons, establishing FAM134B as critical for long-term survival of nociceptive and autonomic ganglion neurons.\",\n      \"method\": \"siRNA knockdown in primary dorsal root ganglion neurons, morphological analysis of cis-Golgi, apoptosis assays; human loss-of-function mutations identified\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function human genetics combined with cellular knockdown and defined phenotypic readouts, replicated across multiple families\",\n      \"pmids\": [\"19838196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FAM134B is an ER-localized reticulophagy receptor that acts as a host restriction factor for dengue virus (DENV) and Zika virus (ZIKV). The flavivirus NS3 protease directly cleaves FAM134B at a single site within its reticulon homology domain (RHD), blocking ER/viral protein-enriched autophagosome formation and suppressing the reticulophagy pathway to promote viral replication.\",\n      \"method\": \"RNAi depletion, viral replication assays, in vitro protease cleavage assay identifying the cleavage site within the RHD, autophagosome formation quantification\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct in vitro cleavage assay combined with RNAi phenotype and autophagosome quantification, multiple viruses tested\",\n      \"pmids\": [\"28102736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The ER-resident lectin chaperone Calnexin (CANX) acts as a co-receptor that recognizes ER-luminal misfolded procollagens and physically interacts with the ER-phagy receptor FAM134B. FAM134B in turn binds autophagosome membrane-associated LC3 and delivers a portion of ER containing both CANX and misfolded procollagen to the lysosome for degradation, constituting selective ER-phagy-based quality control.\",\n      \"method\": \"siRNA/CRISPR-Cas9/knockout gene deletion, co-immunoprecipitation of CANX–FAM134B complex, LC3 binding assay, lysosomal degradation assay in collagen-producing cells\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP establishing CANX–FAM134B complex, multiple genetic tools (siRNA, CRISPR, KO), functional readout (procollagen degradation)\",\n      \"pmids\": [\"30559329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The reticulon homology domain (RHD) of FAM134B contains two wedge-shaped transmembrane helical hairpins and two amphipathic helices that induce membrane curvature and drive membrane remodeling. FAM134B clustering amplifies membrane-shaping effects, and disruption of the RHD structure impairs selective autophagy flux and leads to disease states.\",\n      \"method\": \"Molecular dynamics simulations of RHD in flat and curved membranes, in vitro liposome remodeling assays by electron microscopy, structural modeling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro liposome remodeling validated by EM combined with MD simulation structural model and autophagy flux readouts\",\n      \"pmids\": [\"31147549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAM134B oligomerization through its reticulon-homology domain is required for ER membrane fragmentation in vitro and ER-phagy in vivo. Under ER-stress conditions, CAMK2B phosphorylates the RHD of FAM134B, enhancing FAM134B oligomerization and membrane fragmentation activity. The HSAN patient variant FAM134B G216R exhibits gain-of-function hyperactive self-association and membrane scission, resulting in excessive ER-phagy and sensory neuron death.\",\n      \"method\": \"In vitro membrane fragmentation assays, oligomerization assays, CAMK2B kinase assay with phosphorylation mapping, ER-phagy flux assays in vivo, analysis of patient-derived G216R variant\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of membrane fragmentation, kinase assay with mutagenesis, in vivo ER-phagy quantification, disease variant characterization\",\n      \"pmids\": [\"31930741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The nutrient-responsive transcription factors TFEB and TFE3 directly control ER-phagy by inducing transcription of FAM134B. The TFEB/TFE3–FAM134B axis promotes ER-phagy activation upon prolonged starvation. In chondrocytes, FGF signaling activates JNK-dependent proteasomal degradation of IRS1, which inhibits PI3K–PKB/Akt–mTORC1 and promotes TFEB/TFE3 nuclear translocation to enhance FAM134B transcription.\",\n      \"method\": \"Transcription factor overexpression/knockdown, FAM134B promoter reporter assays, genetic epistasis in chondrocytes, medaka fish FAM134B knockout for in vivo validation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transcriptional reporter assays, epistasis experiments, in vivo vertebrate model, multiple orthogonal methods\",\n      \"pmids\": [\"32716134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RETREG1/FAM134B mediates dual organelle turnover (reticulo-mito-phagy) by interacting with OPA1 (inner mitochondrial membrane protein) when AMFR-destabilized mitochondria form 'mitoplasts' that bring the inner mitochondrial membrane into ER proximity. RETREG1-dependent autophagosomal degradation of both AMFR and OPA1 occurs simultaneously.\",\n      \"method\": \"Co-immunoprecipitation of RETREG1–OPA1 interaction, structured illumination and STED microscopy, autophagosomal degradation assays, stress induction with CCCP\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying OPA1 interaction, super-resolution microscopy, single lab with multiple imaging and biochemical methods\",\n      \"pmids\": [\"32559118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The crystal structure of the FAM134B–GABARAP complex reveals that FAM134B binds to the GABARAP subfamily more strongly than to the LC3 subfamily. FAM134B uses both its LIR core motif and a C-terminal helix to bind GABARAP, and structural determinants for this binding selectivity were identified.\",\n      \"method\": \"Crystal structure determination of FAM134B–GABARAP complex, binding affinity measurements, mutagenesis to identify selectivity determinants\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional binding validation and mutagenesis, single lab but rigorous structural and biochemical approach\",\n      \"pmids\": [\"34854256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FAM134B-RHD spontaneously forms clusters driven by curvature-mediated attractions. At a critical cluster size, FAM134B-RHD induces membrane bud formation. Budding kinetics depend on protein concentration and bilayer asymmetry.\",\n      \"method\": \"Molecular dynamics simulations of FAM134B-RHD clustering and membrane budding\",\n      \"journal\": \"The journal of physical chemistry letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — computational simulation only, no direct in vitro or in vivo experimental validation in this paper\",\n      \"pmids\": [\"33591770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"O-GlcNAc transferase (OGT) directly associates with FAM134B and O-GlcNAcylates it, which reduces FAM134B ubiquitination-mediated degradation, thereby stabilizing FAM134B and enhancing FAM134B-mediated ER-phagy under nutrient deprivation.\",\n      \"method\": \"Co-IP of OGT–FAM134B complex, O-GlcNAcylation site mapping, ubiquitination assays comparing wild-type vs. O-GlcNAc-mutant FAM134B, genetic manipulation in cells and rat IDD model\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, post-translational modification mapping, ubiquitination competition assay, in vivo rat model, single lab\",\n      \"pmids\": [\"36056188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SARS-CoV-2 ORF3a localizes to the ER and induces RETREG1/FAM134B-dependent reticulophagy through the HMGB1–BECN1 (beclin 1) pathway, leading to ER stress and inflammatory responses that facilitate SARS-CoV-2 infection.\",\n      \"method\": \"ORF3a overexpression/localization studies, FAM134B knockdown combined with reticulophagy flux assays, HMGB1–BECN1 pathway epistasis experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis, reticulophagy flux assays, localization studies, single lab\",\n      \"pmids\": [\"35239449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GSDMD promotes autophagy and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity by forming pores on the ER membrane via its N-terminus, thereby activating FAM134B-mediated ER stress. FAM134B then interacts with autophagic protein LC3 to induce cardiac autophagy.\",\n      \"method\": \"GSDMD overexpression/knockdown in cardiomyocytes, ER membrane pore formation assay, co-IP of FAM134B–LC3, autophagy flux assays, in vivo mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of FAM134B–LC3, GSDMD N-terminus pore formation experiment, in vivo and in vitro data, single lab\",\n      \"pmids\": [\"36289195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM134B is acetylated by the acetyltransferase CBP, which elicits intense ER-phagy. FAM134B acetylation subsequently promotes CAMKII-mediated phosphorylation for sustained ER-phagy. Conversely, the deacetylase SIRT7 deacetylates FAM134B to temper its ER-phagy activity and prevent excessive ER degradation.\",\n      \"method\": \"In vitro acetylation assay with CBP, deacetylation assay with SIRT7, phosphorylation assay with CAMKII, ER-phagy flux measurements, mutagenesis of acetylation sites\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assays for acetylation and deacetylation, phosphorylation cascade validation, mutagenesis, functional ER-phagy readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37043189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Coronavirus ORF8 binds FAM134B and ATL3 and undergoes condensation with p62, sequestering FAM134B and ATL3 into ORF8/p62 liquid droplets. This disrupts ER-phagy, facilitates viral double-membrane vesicle (DMV) formation, and activates ER stress.\",\n      \"method\": \"Co-IP of ORF8–FAM134B and ORF8–ATL3 interactions, phase separation/condensate assays, ER-phagy flux assays, DMV formation by EM, FAM134B knockdown/overexpression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of viral–host protein interactions, condensate characterization, ER-phagy flux, single lab\",\n      \"pmids\": [\"36952345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP20 deubiquitinates FAM134B/RETREG1 by specifically cleaving K48- and K63-linked ubiquitin chains, thereby stabilizing RETREG1 and promoting reticulophagy under starvation. USP20 is recruited to the ER through its interaction with VAPs (VAMP-associated proteins), which also facilitate recruitment of WIPI2 to ER subdomains enriched in USP20 and RETREG1.\",\n      \"method\": \"DUB screen, in vitro deubiquitination assay with USP20, K48/K63 ubiquitin chain specificity assays, co-IP of USP20–VAP and USP20–RETREG1 interactions, WIPI2 recruitment assay, reticulophagy flux measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deubiquitination assay, ubiquitin linkage specificity, co-IP of multiple interactions, functional reticulophagy readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38705724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM21 ubiquitinates RETREG1 at K247 and K252, facilitating its proteasomal degradation. CKAP4 competitively binds RETREG1 and shields it from TRIM21-mediated degradation, thereby stabilizing RETREG1 and modulating reticulophagy. Stress-induced TRIM21 upregulation reduces RETREG1 to restore ER stress equilibrium.\",\n      \"method\": \"Co-IP of CKAP4–RETREG1 and TRIM21–RETREG1 interactions, ubiquitination site mapping (K247/K252) by mutagenesis, proteasomal degradation assays, competitive binding assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ubiquitination site mutagenesis, competitive binding assay, degradation rescue experiments, multiple co-IPs, single lab\",\n      \"pmids\": [\"39689859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM134B interacts with DDX3X and prevents its proteasomal degradation by reducing K48-linked polyubiquitination and enhancing K63-linked polyubiquitination of DDX3X. DDX3X stabilization promotes transcription of Rac1, activating AKT signaling in hepatocellular carcinoma. DDX3X also reciprocally increases FAM134B transcriptional activity, forming a positive feedback loop.\",\n      \"method\": \"Co-IP of FAM134B–DDX3X, ubiquitin linkage assays (K48/K63), Rac1 transcription reporter, AKT signaling readouts, FAM134B knockdown in vivo/in vitro\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitin linkage characterization, transcriptional reporter, in vivo HCC model, single lab\",\n      \"pmids\": [\"41198618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM134B interacts with the canonical mitochondrial fission-promoting protein DRP1. Functional depletion of FAM134B leads to local actin rearrangement and reduced DRP1 recruitment onto mitochondria, resulting in mitochondrial hyperfusion. FAM134B levels decrease with aging in rat brains and in Parkinson's disease models.\",\n      \"method\": \"Co-IP of FAM134B–DRP1, fluorescence microscopy of mitochondrial morphology, actin staining, DRP1 recruitment assay upon FAM134B knockdown/KO\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of FAM134B–DRP1, functional mitochondrial morphology readout, actin rearrangement assay, single lab\",\n      \"pmids\": [\"41178515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM134B degrades STIM1 (an ER Ca2+ sensor) via ER-phagy. FAM134B binds STIM1 through its C-terminal cytosolic region; FAM134B knockdown increases STIM1 protein levels by reducing its transport from ER to autolysosomes, accelerates G1-to-S phase transition, and promotes cell proliferation.\",\n      \"method\": \"Co-IP of FAM134B–STIM1, ER-to-autolysosome trafficking assay, cell cycle analysis (G1/S), cell proliferation assay upon FAM134B knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying binding region, trafficking assay, cell cycle readout, single lab\",\n      \"pmids\": [\"39128711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM134B directly interacts with both cholesterol and SCAP (a key regulator of cholesterol biosynthesis). When ER cholesterol is high, FAM134B and SCAP are sequestered by cholesterol-tightened interactions, halting ER-phagy, STING activation, and cholesterol synthesis. Under low cholesterol, FAM134B dissociates from SCAP, allowing SCAP to activate SREBP2 and upregulate cholesterol synthesis, while free FAM134B facilitates ER-phagy through oligomerization or aids STING trafficking.\",\n      \"method\": \"Direct cholesterol-binding assay, co-IP of FAM134B–SCAP complex, cholesterol manipulation experiments, SREBP2 activation assay, ER-phagy and STING trafficking readouts\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct lipid-binding assay, co-IP of FAM134B–SCAP, functional pathway readouts (SREBP2, STING, ER-phagy), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41083602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATF4 forms a heterodimer with CEBPG/C/EBPγ and binds directly to the promoter and enhancer regions of the RETREG1 gene to transcriptionally upregulate RETREG1-mediated reticulophagy in response to lipotoxic stress. RETREG1 knockout mice exhibit more severe hepatic lipotoxicity, confirming protective function.\",\n      \"method\": \"ChIP identifying ATF4 and CEBPG binding sites in RETREG1 promoter/enhancer, co-IP of ATF4–CEBPG heterodimer, RETREG1 promoter reporter assay, retreg1 KO mouse model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP with direct binding site identification, co-IP of transcription factor heterodimer, reporter assay, KO mouse phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40437698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Salmonella Typhimurium inhibits ER-phagy by targeting FAM134B through the bacterial effector protein SopF, preventing FAM134B oligomerization required for efficient ER-phagy. FAM134B knockout raises intracellular Salmonella numbers, while FAM134B activation reduces bacterial burden.\",\n      \"method\": \"FAM134B knockout cells/mice infected with Salmonella, bacterial burden quantification, FAM134B oligomerization assay in presence/absence of SopF, FAM134B activation experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells and mice with defined bacterial burden readout, SopF-FAM134B mechanistic link via oligomerization assay, single lab\",\n      \"pmids\": [\"40133256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MLV glycoGag exploits RETREG1/FAM134B to downregulate SERINC5 at the ER via micro-ER-phagy through an autophagosome-independent process that bypasses ATG3, ATG5, ATG7, BECN1, LC3 lipidation, and PIK3C3. RETREG1 knockout abolishes degradation of ER-retained SERINC5.\",\n      \"method\": \"CRISPR/Cas9 knockout of RETREG1 and autophagy genes (ATG3, ATG5, ATG7, BECN1, PIK3C3), affinity-purified mass spectrometry, SERINC5 degradation assays, co-localization studies\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic CRISPR KO of autophagy pathway components, MS interactome, defined degradation assay, independently described in two papers (PMID 41066524, 40093084)\",\n      \"pmids\": [\"41066524\", \"40093084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"During myogenesis, FAM134B1 is degraded and replaced by FAM134B2. FAM134B2, with its partial reticulon homology domain, drives ER reshaping and reticulophagy during the active differentiation phase. Knockout of both FAM134B isoforms results in aberrant proteome landscape and dilated ER structures, rescued by FAM134B2 re-expression but only partially by FAM134B1.\",\n      \"method\": \"FAM134B double-isoform knockout in myotubes, isoform-specific re-expression rescue experiments, proteomics of ER proteome, EM for ER morphology, ER-phagy flux assays during differentiation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific KO with rescue, proteomics, EM morphology, functional ER-phagy readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39762646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATF6 directly transcriptionally regulates RETREG1 expression in response to LPS-induced ER stress. RETREG1-mediated reticulophagy reduces excessive ER stress via the EIF2AK3 signaling pathway and inhibits MARCH8-dependent MHC-II ubiquitination to maintain antigen presentation in dendritic cells.\",\n      \"method\": \"ATF6 knockout mice, RETREG1 promoter analysis, Cd11ccreRetreg1fl/fl conditional KO mice, MHC-II ubiquitination assay, EIF2AK3 pathway epistasis, DC function assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mice with defined immune phenotype, transcription factor promoter validation, ubiquitination mechanistic assay, single lab\",\n      \"pmids\": [\"41874459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RETREG1-deficiency in dendritic cells activates CASP3–GSDME-dependent pyroptosis during sepsis by inhibiting autophagic degradation of the ERGIC (ER-Golgi intermediate compartment), resulting in abnormal STING1 activation. Genetic downregulation of TMED9 prevents STING1 activation and GSDME-mediated pyroptosis by disrupting ERGIC structure.\",\n      \"method\": \"Cd11ccreRetreg1fl/fl KO mice, ERGIC turnover assays, STING1 activation assays, CASP3/GSDME cleavage readouts, Tmed9 siRNA epistasis, sepsis CLP model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, epistasis with TMED9, defined STING1–GSDME pathway readouts, in vivo sepsis model, single lab\",\n      \"pmids\": [\"41787734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FAM134B interacts with GSTK1 (glutathione S-transferase kappa 1), and silencing GSTK1 further aggravates reduction in reticulophagy and tubular injury that can be partially blocked by RETREG1 overexpression, establishing GSTK1 as a functional partner of RETREG1 in ER homeostasis.\",\n      \"method\": \"Immunoprecipitation coupled with mass spectrometry (IP-MS) identifying GSTK1, co-IP validation, GSTK1 siRNA in proximal tubule-specific Retreg1 KO mice and HK-2 cells, reticulophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS followed by co-IP validation, genetic epistasis in vivo and in vitro, single lab\",\n      \"pmids\": [\"40778749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAM134B overexpression in HeLa cells is sufficient to impair ER homeostasis, accelerate ER degradation, and cause ER stress, the unfolded protein response (UPR), and ER-phagy-dependent cell death. This demonstrates that excessive FAM134B-driven ER-phagy can itself be lethal.\",\n      \"method\": \"FAM134B overexpression in HeLa cells, ER stress markers (UPR), autophagosome number/size quantification, cell death assays, autophagy inhibitor controls\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression gain-of-function with defined ER stress and cell death readouts, pharmacological inhibitor controls, single lab\",\n      \"pmids\": [\"31748416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In hepatocellular carcinoma, FAM134B induces tumorigenesis and epithelial-to-mesenchymal transition (EMT) via the Akt signaling pathway, with subsequent glycogen synthase kinase-3β phosphorylation, β-catenin accumulation, and Snail stabilization.\",\n      \"method\": \"FAM134B gain- and loss-of-function experiments, Akt pathway activator/inhibitor pharmacological rescue, nude mouse xenograft and lung metastasis models, Western blot for pathway components\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiments with Akt activator/inhibitor, in vivo mouse models, defined pathway readouts, single lab\",\n      \"pmids\": [\"30556279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FAM134B physically interacts with CAP1, EB1, CYPB/PPIB, and KDELR2 in colon cancer cells. Exogenous suppression of FAM134B leads to upregulation of EB1 and reduction of KDELR2 expression; elevated EB1 promotes WNT/β-catenin signaling by inactivating the tumor suppressor APC.\",\n      \"method\": \"LC-MS/MS on anti-FAM134B co-immunoprecipitate, Western blot and confocal microscopy validation of FAM134B–EB1, FAM134B–CYPB, FAM134B–KDELR2 interactions, shRNA-mediated FAM134B silencing\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP/MS with orthogonal validation of select interactions, functional pathway readout (EB1/APC/β-catenin), single lab\",\n      \"pmids\": [\"29964340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"m6A modification of FAM134B mRNA is recognized by the m6A reader protein YTHDF2, which binds FAM134B mRNA and reduces its protein level by decreasing mRNA lifetime. A non-m6A FAM134B coding sequence (FAM134B-MUT) is expressed at higher levels, promotes porcine preadipocyte adipogenic differentiation more effectively, and upregulates PPARγ and C/EBPα.\",\n      \"method\": \"m6A site mapping on FAM134B CDS, YTHDF2 RNA immunoprecipitation, wild-type vs. m6A-mutant FAM134B transfection, mRNA stability assay, adipogenic differentiation assays\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA IP establishing YTHDF2–FAM134B mRNA interaction, mRNA stability comparison, functional adipogenesis readout, single lab\",\n      \"pmids\": [\"30506811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FAM134B (wild-type and HSAN2B-linked mutants) interact with LC3/GABARAPL1 in cells, as shown by NanoBiT reporter assay. C-terminal truncated FAM134B mutants show lower protein–protein interaction with LC3 and lower ER-phagy activity. The G216R variant retains LC3/GABARAPL1 interaction to the same extent as wild-type FAM134B.\",\n      \"method\": \"NanoBiT split-luciferase protein–protein interaction reporter assay for FAM134B–LC3/GABARAPL1 interaction, GFP-tagged ER-phagy reporter flux assay, transfection into FAM134B-deficient Neuro2a cells\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NanoBiT quantitative PPI assay for multiple mutants, ER-phagy flux reporter, single lab\",\n      \"pmids\": [\"37273064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM134B and FAM134C cooperate in shaping tubular ER architecture in peripheral axons. Combined Fam134b/Fam134c double knockout (but not Fam134a combinations) in mice causes rapid neuromuscular and somatosensory degeneration, loss of motor and sensory axons, and expanded tubular ER with a transverse ladder-like appearance in long axons, without obvious cortical ER abnormalities.\",\n      \"method\": \"Single and combined FAM134 protein knockout mice, neuromuscular phenotyping, transmission electron microscopy of axonal ER morphology, peripheral nerve histopathology\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double KO genetic epistasis in mice with defined morphological ER phenotype by EM, in vivo neurodegeneration readout\",\n      \"pmids\": [\"39039299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RETREG1/FAM134B is a multi-membrane-spanning ER-phagy receptor that uses its reticulon homology domain (RHD) to induce membrane curvature and, upon oligomerization driven by CAMK2B-mediated phosphorylation and CBP-mediated acetylation (counteracted by SIRT7 deacetylation), fragments ER membranes for lysosomal degradation; its cytosolic LIR motif binds preferentially to the GABARAP subfamily of autophagosomal proteins; it is stabilized by USP20-mediated deubiquitination (removing K48/K63 chains) and O-GlcNAcylation, and is targeted for proteasomal degradation by TRIM21 (K247/K252 ubiquitination) unless protected by CKAP4 binding; it acts in selective ER quality control through a Calnexin co-receptor complex that recognizes misfolded luminal clients (e.g., procollagen), and degrades STIM1 to regulate Ca2+-dependent cell cycle progression; FAM134B–SCAP interactions sense ER cholesterol to couple ER-phagy with SREBP2-driven cholesterol biosynthesis and STING innate immune trafficking; FAM134B also regulates mitochondrial morphology by retaining DRP1 on mitochondria; its RHD is cleaved by flavivirus NS3 proteases and hijacked by bacterial SopF (Salmonella), viral ORF8/p62 condensates (coronaviruses), and retroviral glycoGag (micro-ER-phagy) to subvert ER-phagy; loss-of-function mutations cause hereditary sensory and autonomic neuropathy type IIB (HSAN IIB) due to failure of ER homeostasis in long nociceptive and autonomic neurons, while gain-of-function hyperactive oligomerization (G216R variant) causes excessive ER-phagy and neuronal death.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RETREG1 (FAM134B) is an ER-resident selective autophagy receptor that drives reticulophagy — the targeted lysosomal degradation of endoplasmic reticulum — and is essential for the long-term survival of nociceptive and autonomic neurons, with loss-of-function mutations causing hereditary sensory and autonomic neuropathy [#0, #2]. Its reticulon homology domain (RHD) forms wedge-shaped transmembrane hairpins and amphipathic helices that induce membrane curvature, and upon clustering it amplifies membrane remodeling to fragment ER for capture by autophagosomes [#3, #4]. A cytosolic LIR motif together with a C-terminal helix mediates binding to the autophagosomal ATG8 proteins, with selectivity for the GABARAP subfamily over LC3 [#7, #31]. ER-phagy activity is gated by a dense post-translational and transcriptional control network: CAMK2B phosphorylation and CBP acetylation promote oligomerization and membrane scission, SIRT7 deacetylation tempers it, O-GlcNAcylation and USP20-mediated removal of K48/K63 ubiquitin chains stabilize the receptor, and TRIM21 ubiquitination at K247/K252 drives proteasomal turnover unless CKAP4 binding shields it [#4, #12, #9, #14, #15]; nutrient- and stress-responsive transcription factors TFEB/TFE3, ATF4–CEBPG, ATF6, and others induce RETREG1 expression [#5, #20, #24]. Functionally, RETREG1 executes selective ER quality control via a Calnexin co-receptor complex that delivers misfolded luminal procollagen for degradation, and degrades the ER Ca2+ sensor STIM1 to restrain G1-to-S cell cycle progression [#2, #18]. Through direct cholesterol and SCAP binding it couples ER-phagy to SREBP2-driven cholesterol synthesis and STING trafficking [#19], and it also influences mitochondrial morphology by promoting DRP1 recruitment for fission [#17]. RETREG1 is exploited or restricted at host–pathogen interfaces: flavivirus NS3 protease cleaves its RHD, Salmonella SopF blocks its oligomerization, coronavirus ORF8/p62 condensates sequester it, and retroviral glycoGag hijacks it for autophagosome-independent micro-ER-phagy of SERINC5 [#1, #21, #13, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established RETREG1/FAM134B as a disease gene and as essential for neuronal survival, before any molecular function was known.\",\n      \"evidence\": \"Human loss-of-function mutations and siRNA knockdown in primary dorsal root ganglion neurons with Golgi morphology and apoptosis readouts\",\n      \"pmids\": [\"19838196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular mechanism for the survival defect\", \"Golgi phenotype precedes identification of an ER-phagy role\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified RETREG1 as an ER-phagy receptor and a flavivirus restriction factor by showing NS3 protease cleaves its reticulon homology domain to disable the pathway.\",\n      \"evidence\": \"RNAi viral replication assays and in vitro protease cleavage assay mapping a single RHD cleavage site\",\n      \"pmids\": [\"28102736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the RHD remodels membranes\", \"Cargo selectivity not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined selective ER quality control by showing Calnexin acts as a luminal co-receptor delivering misfolded procollagen to the lysosome through RETREG1–LC3 coupling.\",\n      \"evidence\": \"Reciprocal co-IP of CANX–FAM134B, LC3 binding and lysosomal procollagen degradation assays with siRNA/CRISPR/KO tools\",\n      \"pmids\": [\"30559329\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How luminal misfolding signals across the membrane to the cytosolic receptor unresolved\", \"Generality beyond procollagen clients untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided the structural basis for membrane fragmentation, showing the RHD's transmembrane hairpins and amphipathic helices induce curvature amplified by clustering.\",\n      \"evidence\": \"Molecular dynamics simulations plus in vitro liposome remodeling validated by electron microscopy\",\n      \"pmids\": [\"31147549\", \"33591770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the full RHD not determined\", \"Coupling of clustering to autophagosome capture in vivo not directly shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed oligomerization is the key activating step and is regulated by CAMK2B phosphorylation, and that a hyperactive patient variant (G216R) drives excessive ER-phagy and neuron death — establishing gain-of-function pathology distinct from loss-of-function disease.\",\n      \"evidence\": \"In vitro membrane fragmentation and oligomerization assays, CAMK2B kinase assay with phospho-mapping, in vivo ER-phagy flux, G216R variant analysis\",\n      \"pmids\": [\"31930741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream trigger of CAMK2B activation at the ER unclear\", \"How G216R alters self-association at the structural level not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected RETREG1 to nutrient-responsive transcriptional control via the TFEB/TFE3 axis downstream of mTORC1.\",\n      \"evidence\": \"Promoter reporter assays, transcription factor manipulation, chondrocyte epistasis, medaka FAM134B knockout\",\n      \"pmids\": [\"32716134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TFEB/TFE3 induction occurs in neurons unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved ATG8 selectivity, showing RETREG1 binds the GABARAP subfamily more strongly than LC3 using both LIR core and a C-terminal helix.\",\n      \"evidence\": \"Crystal structure of FAM134B–GABARAP complex with affinity measurements and selectivity mutagenesis\",\n      \"pmids\": [\"34854256\", \"37273064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of GABARAP preference for cargo-specific ER-phagy not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded the activation code, showing CBP acetylation primes intense ER-phagy and licenses CAMKII phosphorylation, while SIRT7 deacetylation restrains over-degradation.\",\n      \"evidence\": \"In vitro acetylation/deacetylation/phosphorylation assays with site mutagenesis and ER-phagy flux readouts\",\n      \"pmids\": [\"37043189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimuli controlling the CBP/SIRT7 balance in vivo unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established opposing ubiquitin-based stability control: USP20 (via VAP recruitment) deubiquitinates and stabilizes the receptor, whereas TRIM21 ubiquitinates K247/K252 for degradation unless CKAP4 competitively protects it.\",\n      \"evidence\": \"In vitro deubiquitination with K48/K63 specificity, DUB screen, co-IPs, WIPI2 recruitment, ubiquitination site mutagenesis and competitive binding/degradation rescue\",\n      \"pmids\": [\"38705724\", \"39689859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How USP20 and TRIM21 activities are balanced under a given stress unresolved\", \"O-GlcNAcylation stabilization mechanism (36056188) is Medium-confidence\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened the substrate repertoire and organelle reach: RETREG1 degrades STIM1 to gate the cell cycle and influences mitochondrial fission via DRP1 recruitment.\",\n      \"evidence\": \"Co-IPs (STIM1, DRP1, OPA1), ER-to-autolysosome trafficking, cell cycle analysis, mitochondrial morphology imaging\",\n      \"pmids\": [\"39128711\", \"41178515\", \"32559118\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DRP1 and OPA1 links rest on single-lab co-IP plus imaging\", \"Direct vs. indirect effect on mitochondrial fission not disentangled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified RETREG1 as a cholesterol/SCAP sensor that couples ER-phagy to sterol biosynthesis and STING trafficking, integrating lipid metabolism with ER turnover.\",\n      \"evidence\": \"Direct cholesterol-binding assay, FAM134B–SCAP co-IP, cholesterol manipulation, SREBP2 and STING readouts\",\n      \"pmids\": [\"41083602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of cholesterol/SCAP sensing unresolved\", \"Physiological tissue context of sterol coupling untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined RETREG1 as a broadly targeted node in host–pathogen conflict, hijacked by bacteria and viruses through distinct anti-oligomerization, sequestration, and micro-ER-phagy mechanisms.\",\n      \"evidence\": \"FAM134B KO cells/mice with bacterial burden and SopF oligomerization assays, ORF8/p62 condensate assays, CRISPR KO of autophagy genes with SERINC5 degradation and interactome MS\",\n      \"pmids\": [\"40133256\", \"36952345\", \"41066524\", \"40093084\", \"35239449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether autophagosome-independent micro-ER-phagy operates outside glycoGag context unknown\", \"Shared structural determinant exploited by diverse pathogens not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended transcriptional and physiological control through ER-stress factors (ATF4–CEBPG, ATF6) and immune/tissue functions, including dendritic cell antigen presentation, sepsis pyroptosis, and protection from hepatic lipotoxicity.\",\n      \"evidence\": \"ChIP/promoter reporter assays, conditional and global KO mouse models, ERGIC turnover and STING1/GSDME readouts\",\n      \"pmids\": [\"40437698\", \"41874459\", \"41787734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specific transcriptional logic across stressors not unified\", \"Several immune phenotypes from single-lab conditional KOs\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated isoform specialization, showing FAM134B2 replaces FAM134B1 during myogenesis to drive ER reshaping, and that FAM134B/FAM134C cooperate to maintain axonal tubular ER.\",\n      \"evidence\": \"Isoform-specific double KO with rescue, proteomics and EM in myotubes; combined FAM134b/c KO mouse neurodegeneration with EM of axonal ER\",\n      \"pmids\": [\"39762646\", \"39039299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional non-equivalence of paralogs mechanistically unexplained\", \"Why neurons are uniquely vulnerable not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple regulatory layers — phosphorylation, acetylation, ubiquitination, O-GlcNAcylation, lipid sensing, and transcription — are integrated to set RETREG1 activity in a given cell type and stress, and how this dictates the loss- vs. gain-of-function disease balance, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking the regulatory inputs\", \"Cell-type-specific thresholds for protective vs. lethal ER-phagy undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 4, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 7, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 2, 3, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 7, 18]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2, 4, 14, 22]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [12, 20, 24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 9, 14, 15]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [19, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 24, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 21, 22]}\n    ],\n    \"complexes\": [\n      \"FAM134B–Calnexin ER-phagy co-receptor complex\"\n    ],\n    \"partners\": [\n      \"CANX\",\n      \"GABARAP\",\n      \"SCAP\",\n      \"USP20\",\n      \"TRIM21\",\n      \"CKAP4\",\n      \"STIM1\",\n      \"DRP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}