{"gene":"RTN3","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2017,"finding":"Full-length RTN3 (long isoform) acts as a selective autophagy receptor for ER-phagy of tubular ER. Oligomerization of the long isoform is sufficient to trigger fragmentation of ER tubules. The long N-terminal region of RTN3 contains multiple LC3-interacting regions (LIR motifs), and binding to LC3s/GABARAPs is essential for tubule fragmentation and lysosomal delivery. RTN3-mediated ER-phagy requires conventional autophagy components but is independent of FAM134B.","method":"Selective autophagy assays, LC3 co-immunoprecipitation, LIR motif identification/mutagenesis, live imaging, lysosomal delivery assays, genetic epistasis with FAM134B KO","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis of LIR motifs, live imaging, genetic epistasis), published in peer-reviewed journal, defines unique function among reticulon family members","pmids":["28617241"],"is_preprint":false},{"year":2006,"finding":"RTN3 physically interacts with BACE1 via the transmembrane region of BACE1, and overexpression of RTN3 inhibits BACE1 activity, reducing Abeta40 and Abeta42 secretion by 30–50%. RTN3 also interacts with BACE2.","method":"Co-immunoprecipitation in SH-SY5Y and HEK293 cells, proteomic identification, BACE1 ectodomain deletion mutant binding assay, Abeta secretion assay","journal":"The European journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in multiple cell lines, functional Abeta secretion assay, domain mapping with BACE1 truncation mutant, replicated by multiple subsequent studies","pmids":["16965550"],"is_preprint":false},{"year":2007,"finding":"RTN3 adopts an omega-shaped membrane topology with two long transmembrane domains and both N- and C-termini facing the cytosolic side. The first transmembrane domain dictates membrane integration. Subtle alterations in this topology disrupt RTN3 binding to BACE1 and abolish its inhibitory effects on BACE1 activity.","method":"Membrane topology mapping assays, site-directed mutagenesis, co-immunoprecipitation, BACE1 activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct topology determination with mutagenesis linked to functional consequence (BACE1 binding and inhibition), multiple orthogonal approaches in single study","pmids":["17699523"],"is_preprint":false},{"year":2014,"finding":"RTN3 deficiency in mice increases BACE1 protein levels and enhances APP processing at the beta-secretase site, leading to increased amyloid deposition in Alzheimer's mouse models. This demonstrates RTN3 negatively regulates BACE1 protein stability and activity in vivo.","method":"RTN3-null mouse generation, biochemical analysis of BACE1 levels and APP processing, histological analysis of amyloid deposition in RTN3-null x AD model mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse model with defined molecular phenotype (BACE1 levels, APP processing) and histological readout, replicated by in vivo AD model crossing","pmids":["25319692"],"is_preprint":false},{"year":2009,"finding":"RTN3 overexpression reduces amyloid deposition in cortex and hippocampus of APP/PS1 mice, and this is associated with retention of BACE1 in the ER compartment where APP cleavage is less favored, altering BACE1 intracellular trafficking. RTN3 aggregates in dystrophic neurites offset this inhibitory effect.","method":"Triple transgenic mouse model (RTN3 overexpressor x APP/PS1), amyloid burden quantification, BACE1 intracellular localization studies, immunohistochemistry","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic mouse model with rigorous quantification, mechanistic link to BACE1 ER retention, complementary to RTN3-null findings","pmids":["19625507"],"is_preprint":false},{"year":2005,"finding":"RTN3 (identified as ASYIP) forms a complex with ASY/Nogo-B (RTN4) in human cells; both hydrophobic transmembrane regions of RTN3 are required for this association. RTN3 co-localizes with ASY/Nogo-B in the ER, as shown by immunofluorescence. RTN3 contains a double-lysine ER retrieval motif at its C-terminus.","method":"Yeast two-hybrid cloning, co-immunoprecipitation in human cells, immunofluorescence co-localization, deletion/mutational analysis","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and co-localization with mutational analysis in single lab; yeast two-hybrid corroborated by cell-based assays","pmids":["12811824"],"is_preprint":false},{"year":2005,"finding":"RTN3 overexpression triggers ER overload response (EOR)-induced apoptosis through depletion of ER Ca2+ stores and sustained elevation of cytosolic Ca2+, activating caspase-12 and mitochondrial dysfunction. Overexpressed RTN3 also induces iNOS upregulation via Ca2+ release and reactive oxygen intermediates as a protective feedback.","method":"Overexpression in HeLa cells, Ca2+ measurement, caspase-12 activation assay, mitochondrial dysfunction assay, iNOS reporter/Western blot","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (Ca2+ flux, caspase activation, mitochondrial dysfunction) from single lab with overexpression model","pmids":["15799019"],"is_preprint":false},{"year":2006,"finding":"Endogenous FADD is recruited by ER-bound RTN3 to the ER membrane, initiating caspase-8 cascade including Bid processing and cytochrome c release from mitochondria. Dominant-negative FADD (DD domain) abolishes these RTN3-mediated caspase-8 cascade events. Endogenous FADD is also recruited by endogenous RTN3 upon tunicamycin stimulation.","method":"Co-immunoprecipitation of endogenous proteins, dominant-negative FADD overexpression, caspase-8 activation assay, cytochrome c release assay, tunicamycin stimulation","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous Co-IP, functional epistasis with dominant-negative FADD, multiple caspase pathway readouts; single lab","pmids":["17031492"],"is_preprint":false},{"year":2007,"finding":"RTN3 interacts with Bcl-2 on the ER membrane. Overexpressed Bcl-2 reduces RTN3-induced apoptosis. Increased endogenous RTN3 in the microsomal fraction (upon tunicamycin) enhances Bcl-2 localization to both microsomal and mitochondrial fractions, potentiating Bcl-2 anti-apoptotic activity.","method":"Co-immunoprecipitation, subcellular fractionation, apoptosis assay, Bcl-2 stable overexpression in HeLa cells","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional consequence (Bcl-2 redistribution and anti-apoptotic effect), subcellular fractionation, single lab","pmids":["17379544"],"is_preprint":false},{"year":2009,"finding":"RTN3 overexpression upregulates death receptor DR5 surface protein and downregulates c-FLIP, sensitizing cells to TRAIL-mediated apoptosis. DR5 siRNA or DR5/Fc chimera blocks RTN3-mediated TRAIL sensitization, establishing DR5 as the primary mediator. RTN3 also enhances TNF-alpha and Fas-mediated apoptosis.","method":"Stable RTN3 overexpression, DR5 siRNA knockdown, DR5/Fc chimera blocking, flow cytometry for DR4/DR5 surface levels, TRAIL apoptosis assay, c-FLIP Western blot","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis with DR5 siRNA and blocking chimera, multiple apoptosis readouts, single lab","pmids":["19250737"],"is_preprint":false},{"year":2009,"finding":"RTN3 (CRELD1 binding partner) is recruited by CRELD1 interaction, which shifts RTN3 localization from the ER to the plasma membrane and moderately decreases RTN3-mediated apoptotic activity. CRELD1 interaction also partially suppresses tunicamycin-induced apoptosis.","method":"Co-immunoprecipitation of ectopic and endogenous RTN3 with CRELD1, immunofluorescence localization, apoptosis assay","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and localization without full mechanistic follow-up; single lab","pmids":["19521671"],"is_preprint":false},{"year":2017,"finding":"RTN3 expression is induced by cold/hypothermia and is a downstream effector of RBM3-mediated neuroprotection. RBM3 binds to RTN3 mRNA to drive increased RTN3 translation. RTN3 knockdown in mice eliminates cooling-induced neuroprotection; lentiviral RTN3 overexpression independently prevents synaptic loss and cognitive deficits in a mouse neurodegeneration model downstream of RBM3.","method":"Translatome profiling, RBM3 RNA-binding assay, RTN3 knockdown in mice (lentiviral), lentiviral RTN3 overexpression in mouse neurodegeneration model, cognitive/synaptic phenotyping","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo models (KD and OE), RBM3 binding assay, defined neuroprotective phenotype with mechanistic link; multiple orthogonal approaches","pmids":["28238655"],"is_preprint":false},{"year":2018,"finding":"RTN3 interacts with HSPA5 (GRP78/BiP), and this interaction increases SREBP-1c and AMPK activity, promoting triglyceride biosynthesis and lipid droplet expansion. RTN3 transgenic mice develop obesity and hypertriglyceridemia; RTN3-null mice have reduced triglyceride accumulation.","method":"RTN3 transgenic and null mouse models, co-immunoprecipitation with HSPA5, SREBP-1c and AMPK activity assays, 3T3L1 cell culture, C. elegans genetic models","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with HSPA5, transgenic and null mouse phenotypes, in vitro cell culture; single lab, multiple model systems","pmids":["29716941"],"is_preprint":false},{"year":2018,"finding":"BAP31 is a binding partner of RTN3 that stabilizes RTN3 monomer. BAP31 knockout in hippocampal neurons decreases RTN3 monomer availability, increases RTN3 aggregates, and consequently enhances BACE1-mediated APP processing and amyloid plaque formation.","method":"Co-immunoprecipitation of BAP31 and RTN3, conditional BAP31-KO mouse crossed with APP/PS1 AD model, primary hippocampal neuron culture, Western blot for RTN3 aggregates and BACE1 processing","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, conditional KO mouse with AD model crossing, mechanistic link to RTN3 stability and BACE1 processing; single lab","pmids":["30596517"],"is_preprint":false},{"year":2021,"finding":"RTN3 is upregulated during RNA viral infection and acts as a negative regulator of RIG-I antiviral signaling. RTN3 aggregates on the ER and interacts with both TRIM25 and RIG-I, impairing K63-linked polyubiquitination of RIG-I, resulting in inhibition of IRF3 and NF-κB activation. RTN3 overexpression in mice reduces neutrophil infiltration and inflammatory damage upon VSV challenge.","method":"Co-immunoprecipitation of RTN3 with TRIM25 and RIG-I, ubiquitination assay (K63-linked), IRF3/NF-κB reporter assay, RTN3-overexpressing mouse model challenged with VSV, immunohistochemistry","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with two partners (TRIM25 and RIG-I), direct ubiquitination assay, in vivo mouse model with defined inflammatory phenotype; multiple orthogonal methods","pmids":["34313226"],"is_preprint":false},{"year":2022,"finding":"RTN3 deficiency in kidney proximal tubular epithelial cells activates the IGF2-JAK2-STAT3 pathway through interaction with GPBP1, leading to collagen biosynthesis upregulation and mitochondrial dysfunction, phenocopying chronic kidney disease and fibrosis.","method":"RTN3-null mouse model, co-immunoprecipitation with GPBP1, IGF2-JAK2-STAT3 pathway analysis, primary proximal tubular epithelial cells, HEK293 cells in vitro","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model, Co-IP with GPBP1, pathway activation assays; single lab","pmids":["35596061"],"is_preprint":false},{"year":2023,"finding":"RTN3 directly binds FABP5 to facilitate directed transport of fatty acids to the ER, promoting lipid droplet biogenesis in a DGAT2-dependent manner in cardiomyocytes. Lipid overload-induced RTN3 upregulation is driven by C/EBPα, which binds the RTN3 promoter.","method":"Co-immunoprecipitation of RTN3 and FABP5, gain/loss-of-function in cardiomyocytes, DGAT2 inhibition, C/EBPα promoter binding assay (ChIP), HFD mouse model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct Co-IP, DGAT2 epistasis, ChIP for transcriptional regulation; multiple methods in single lab","pmids":["38017147"],"is_preprint":false},{"year":2023,"finding":"RTN3 interacts with GRP78 (HSPA5) in hepatocytes, and increased RTN3 inhibits the AMPK-IDH2 pathway, leading to mitochondrial dysfunction and lipid accumulation phenocopying NAFLD. RTN3 knockout relieves fatty liver and mitochondrial dysfunction.","method":"Co-immunoprecipitation with GRP78, AMPK and IDH2 activity assays, RTN3-null mouse model, primary hepatocytes, L02 cell line, C. elegans strain, HFD model","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with GRP78, pathway activity assays, KO mouse and multiple cell models; single lab","pmids":["36925557"],"is_preprint":false},{"year":2024,"finding":"RTN3 deficiency disrupts the RTN3-HSPA9-VDAC2 complex at mitochondria-associated membranes (MAMs), impairing ER-mitochondrion contact and causing mitochondrial dysfunction that exacerbates cisplatin-induced acute kidney injury.","method":"Co-immunoprecipitation of RTN3, HSPA9, and VDAC2, RTN3-null mouse model with cisplatin treatment, primary renal tubular epithelial cells, HK2 cell line, MAM analysis","journal":"Mitochondrion","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of three-protein complex, KO mouse with defined phenotype; single lab","pmids":["38336146"],"is_preprint":false},{"year":2024,"finding":"In socially isolated AD mice, RTN3 aggregates in presynaptic regions and disturbs mossy fibre bouton formation by recruiting multiple mitochondrial and vesicle-related proteins. RTN3 aggregation also recruits PP2A B subunits, suppressing PP2A activity and inducing tau hyperphosphorylation, which further elevates RTN3 in a feedforward cycle.","method":"RTN3 interactome analysis (AI-assisted molecular docking), in vivo mouse model (social isolation + AD), PP2A activity assay, tau phosphorylation analysis, senktide treatment to disrupt RTN3 interactions","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with defined synaptic and tau phenotypes, PP2A activity assay, interactome analysis; single lab with multiple readouts","pmids":["38011644"],"is_preprint":false},{"year":2025,"finding":"RTN3 interacts with CRTH2 in lung fibroblasts; RTN3 deficiency reduces ER-anchored CRTH2 (which antagonizes collagen biosynthesis) and simultaneously reduces autophagy-mediated degradation of CRTH2 in macrophages (where CRTH2 activates profibrotic differentiation), resulting in aggravated pulmonary fibrosis.","method":"Co-immunoprecipitation of RTN3 and CRTH2, RTN3-null mouse model with bleomycin treatment, lung fibroblast and alveolar macrophage studies, autophagy assay","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KO mouse with fibrosis phenotype, mechanistic dissection in two cell types; single lab","pmids":["39972424"],"is_preprint":false},{"year":2011,"finding":"RTN3 interacts with Ras at the ER, as demonstrated by confocal co-localization and co-immunoprecipitation. RTN3 upregulation during HSV mutant infection correlates with decreased Ras on the plasma membrane.","method":"Confocal co-localization, co-immunoprecipitation, siRNA knockdown of RTN3, Western blot and flow cytometry for Ras distribution","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and co-localization, correlative context, single lab","pmids":["17218780"],"is_preprint":false},{"year":2026,"finding":"RTN3 directly interacts with DHCR7 and promotes its ubiquitination. RTN3 downregulation stabilizes DHCR7, elevating cholesterol concentration and activating the EGFR/ERK pathway in thyroid cancer.","method":"Co-immunoprecipitation of RTN3 and DHCR7, ubiquitination assay, RTN3 loss-of-function experiments, EGFR/ERK pathway activity assay, Simvastatin rescue","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, direct ubiquitination assay, pathway rescue with statin; single lab","pmids":["41813657"],"is_preprint":false},{"year":2023,"finding":"RTN3 and RTN4 are required for the formation of SARS-CoV-2 replication organelles through direct interaction with viral proteins NSP3 and NSP4.","method":"Co-immunoprecipitation/interaction studies with viral NSP3/NSP4, RTN3/RTN4 loss-of-function, replication organelle formation assay (as described by Williams et al., cited in this commentary)","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction with viral proteins, functional replication organelle assay (per cited primary study); this entry is a commentary citing the primary research","pmids":["37318453"],"is_preprint":false},{"year":2018,"finding":"RTN3 variant T39M (c.116C>T) found in early-onset AD patients causes impaired axonal transport of BACE1 when overexpressed in cultured neurons. The c.-8G>T 5'-UTR variant reduces RTN3 expression.","method":"Luciferase reporter assay for expression, kymograph analysis of BACE1-RFP particle mobility in neurons transfected with WT or variant RTN3","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging (kymography) of BACE1 transport, reporter assay for expression; single lab, disease-variant functional characterization","pmids":["29356939"],"is_preprint":false}],"current_model":"RTN3 is an ER-resident reticulon protein with an omega-shaped transmembrane topology that serves multiple mechanistic roles: (1) as a selective ER-phagy receptor for tubular ER degradation via LIR-motif-dependent interaction with LC3s/GABARAPs; (2) as a negative regulator of BACE1 activity through direct transmembrane interaction, retaining BACE1 in the ER and reducing amyloid-beta production; (3) as a modulator of lipid metabolism through interactions with HSPA5/GRP78, FABP5, and DHCR7; (4) as a negative regulator of RIG-I antiviral signaling by impairing TRIM25-mediated K63 ubiquitination; and (5) as an ER-based scaffold that recruits apoptotic machinery (FADD/caspase-8) and interacts with Bcl-2, PP2A, and multiple other partners to modulate cell survival, mitochondrial function, and ER stress responses."},"narrative":{"mechanistic_narrative":"RTN3 is an ER-resident reticulon protein that shapes tubular ER and acts as a multifunctional regulator of membrane dynamics, lipid metabolism, and cell-fate signaling [PMID:28617241, PMID:17699523]. It adopts an omega-shaped membrane topology with two long transmembrane domains and cytosolically exposed N- and C-termini, a configuration whose integrity is required for its protein interactions [PMID:17699523]. The full-length long isoform functions as a selective ER-phagy receptor: its oligomerization fragments ER tubules, and multiple N-terminal LIR motifs bind LC3s/GABARAPs to deliver tubular ER to lysosomes through conventional autophagy machinery independently of FAM134B [PMID:28617241]. RTN3 is a direct negative regulator of the beta-secretase BACE1, binding it via the BACE1 transmembrane region, retaining it in the ER where APP cleavage is disfavored, and limiting amyloid-beta production; loss of RTN3 raises BACE1 levels and amyloid deposition in vivo while its overexpression reduces amyloid burden [PMID:16965550, PMID:25319692, PMID:19625507]. RTN3 modulates lipid homeostasis through interactions with HSPA5/GRP78, FABP5, and DHCR7, influencing triglyceride and lipid-droplet biogenesis and cholesterol/EGFR signaling [PMID:29716941, PMID:38017147, PMID:41813657]. It additionally restrains RIG-I antiviral signaling by impairing TRIM25-mediated K63-linked ubiquitination of RIG-I [PMID:34313226], and serves as an ER scaffold that recruits apoptotic machinery and partners including FADD/caspase-8 and Bcl-2 to tune cell survival and ER stress responses [PMID:17031492, PMID:17379544]. A neuroprotective role downstream of cold-induced RBM3 has also been established in vivo [PMID:28238655].","teleology":[{"year":2005,"claim":"Established that RTN3 partners with another reticulon and resides in the ER, defining its baseline membrane localization and self-association behavior.","evidence":"Yeast two-hybrid, Co-IP, immunofluorescence co-localization with ASY/Nogo-B (RTN4) in human cells","pmids":["12811824"],"confidence":"Medium","gaps":["Functional consequence of the RTN3-RTN4 complex not defined","ER retrieval motif role not tested for trafficking"]},{"year":2005,"claim":"Showed that excess RTN3 can drive ER-stress apoptosis, raising the question of how an ER-shaping protein controls cell fate.","evidence":"Overexpression in HeLa cells with Ca2+ flux, caspase-12 activation, and mitochondrial dysfunction readouts","pmids":["15799019"],"confidence":"Medium","gaps":["Overexpression model may not reflect endogenous signaling","Direct effectors of the ER overload response not identified"]},{"year":2006,"claim":"Identified RTN3 as a direct binding partner and negative regulator of BACE1, linking it to amyloid-beta production.","evidence":"Reciprocal Co-IP in SH-SY5Y/HEK293, BACE1 ectodomain deletion mapping, Abeta secretion assay","pmids":["16965550"],"confidence":"High","gaps":["Endogenous stoichiometry of the interaction unknown","Mechanism of activity inhibition vs. trafficking control not separated"]},{"year":2006,"claim":"Connected ER-bound RTN3 to extrinsic apoptotic signaling by showing it recruits FADD and triggers a caspase-8 cascade.","evidence":"Endogenous Co-IP, dominant-negative FADD epistasis, caspase-8/cytochrome c assays under tunicamycin","pmids":["17031492"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","How an ER-resident protein engages canonical death-receptor adaptors mechanistically unclear"]},{"year":2007,"claim":"Resolved the omega-shaped topology of RTN3 and tied it directly to BACE1 binding, providing the structural basis for its inhibitory function.","evidence":"Membrane topology mapping plus site-directed mutagenesis linked to BACE1 binding and activity","pmids":["17699523"],"confidence":"High","gaps":["High-resolution structure not determined","Oligomerization geometry not defined"]},{"year":2007,"claim":"Extended RTN3's apoptotic role by showing it interacts with Bcl-2 and redistributes it, integrating pro- and anti-apoptotic balance at the ER.","evidence":"Co-IP, subcellular fractionation, Bcl-2 overexpression apoptosis assays in HeLa","pmids":["17379544"],"confidence":"Medium","gaps":["Direct binding interface not mapped","Relationship to FADD-driven pathway unresolved"]},{"year":2009,"claim":"Demonstrated in vivo that RTN3 overexpression retains BACE1 in the ER and lowers amyloid burden, establishing trafficking control as a mechanism.","evidence":"RTN3 x APP/PS1 transgenic mice with amyloid quantification and BACE1 localization studies","pmids":["19625507"],"confidence":"High","gaps":["Effect of RTN3 aggregates that offset inhibition not fully mechanistically dissected"]},{"year":2009,"claim":"Linked RTN3 to death-receptor sensitization by showing it upregulates DR5 and downregulates c-FLIP.","evidence":"Stable overexpression, DR5 siRNA and DR5/Fc blocking, TRAIL apoptosis assays","pmids":["19250737"],"confidence":"Medium","gaps":["Transcriptional vs. post-translational basis of DR5 upregulation unknown","Single-lab overexpression study"]},{"year":2014,"claim":"Provided loss-of-function genetic proof that RTN3 negatively regulates BACE1 stability and amyloid deposition in vivo.","evidence":"RTN3-null mice and crosses to AD models with BACE1/APP processing biochemistry and histology","pmids":["25319692"],"confidence":"High","gaps":["Molecular basis for BACE1 protein stabilization on RTN3 loss not defined"]},{"year":2017,"claim":"Defined RTN3 as a selective ER-phagy receptor, assigning it a distinct catabolic function within the reticulon family.","evidence":"Selective autophagy assays, LIR-motif mutagenesis, LC3 Co-IP, live imaging, FAM134B-KO epistasis","pmids":["28617241"],"confidence":"High","gaps":["Signal triggering RTN3 oligomerization/activation unknown","Cargo selectivity determinants not fully mapped"]},{"year":2017,"claim":"Placed RTN3 downstream of cold-induced RBM3 as a translationally regulated neuroprotective effector.","evidence":"Translatome profiling, RBM3 RNA-binding assay, RTN3 knockdown and lentiviral overexpression in mouse neurodegeneration models","pmids":["28238655"],"confidence":"High","gaps":["Molecular mechanism by which RTN3 prevents synaptic loss not resolved","Relation to ER-phagy or BACE1 functions unclear"]},{"year":2018,"claim":"Connected RTN3 to lipid metabolism through HSPA5 binding driving triglyceride biosynthesis and lipid-droplet expansion.","evidence":"RTN3 transgenic and null mice, HSPA5 Co-IP, SREBP-1c/AMPK assays, 3T3L1 and C. elegans models","pmids":["29716941"],"confidence":"Medium","gaps":["Direct mechanistic step from HSPA5 binding to SREBP-1c activation not defined","Single-lab study"]},{"year":2018,"claim":"Identified BAP31 as a stabilizer of the RTN3 monomer, linking RTN3 aggregation state to BACE1-driven amyloid processing.","evidence":"Co-IP, conditional BAP31-KO mice crossed with APP/PS1, hippocampal neuron culture","pmids":["30596517"],"confidence":"Medium","gaps":["Why monomer vs. aggregate differentially regulates BACE1 not mechanistically resolved"]},{"year":2018,"claim":"Linked an RTN3 coding variant and reduced expression to early-onset AD by impairing BACE1 axonal transport.","evidence":"Luciferase reporter for 5'-UTR variant and kymography of BACE1-RFP mobility in neurons","pmids":["29356939"],"confidence":"Medium","gaps":["Pathogenicity of T39M not established beyond cell-based assays","No family co-segregation data in the timeline"]},{"year":2021,"claim":"Established RTN3 as a negative regulator of innate antiviral signaling by impairing TRIM25-mediated K63 ubiquitination of RIG-I.","evidence":"Co-IP with TRIM25 and RIG-I, K63-linked ubiquitination assay, IRF3/NF-kB reporters, VSV challenge in RTN3-overexpressing mice","pmids":["34313226"],"confidence":"High","gaps":["How RTN3 aggregation sequesters the TRIM25/RIG-I complex structurally unclear"]},{"year":2022,"claim":"Showed RTN3 deficiency drives renal fibrosis via GPBP1 interaction and IGF2-JAK2-STAT3 activation.","evidence":"RTN3-null mice, GPBP1 Co-IP, pathway analysis in proximal tubular cells","pmids":["35596061"],"confidence":"Medium","gaps":["Direct effect of RTN3 on GPBP1 function not defined","Single-lab finding"]},{"year":2023,"claim":"Extended RTN3's lipid role to cardiomyocytes by direct FABP5 binding driving fatty-acid delivery and DGAT2-dependent lipid-droplet biogenesis.","evidence":"RTN3-FABP5 Co-IP, gain/loss-of-function, DGAT2 inhibition, C/EBPalpha ChIP, HFD mice","pmids":["38017147"],"confidence":"Medium","gaps":["Whether FABP5 transport mechanism generalizes beyond cardiomyocytes untested"]},{"year":2023,"claim":"Implicated RTN3-GRP78 interaction in hepatic mitochondrial dysfunction and steatosis via AMPK-IDH2 suppression.","evidence":"GRP78 Co-IP, AMPK/IDH2 assays, RTN3-null mice, hepatocyte/L02/C. elegans models","pmids":["36925557"],"confidence":"Medium","gaps":["Relationship to the HSPA5-SREBP-1c lipid axis not reconciled","Single-lab study"]},{"year":2023,"claim":"Showed RTN3 (with RTN4) is co-opted by SARS-CoV-2 to build replication organelles via NSP3/NSP4 interaction.","evidence":"Interaction studies with viral NSP3/NSP4 and replication organelle formation assay (commentary citing primary study)","pmids":["37318453"],"confidence":"Medium","gaps":["Entry is a commentary; primary mechanistic detail limited","Specific RTN3 contribution vs. RTN4 not separated"]},{"year":2024,"claim":"Defined an RTN3-HSPA9-VDAC2 complex at MAMs mediating ER-mitochondrion contact and protecting against kidney injury.","evidence":"Three-protein Co-IP, RTN3-null mice with cisplatin, MAM analysis in renal tubular cells","pmids":["38336146"],"confidence":"Medium","gaps":["Stoichiometry and assembly order of the complex unknown","Single-lab study"]},{"year":2024,"claim":"Linked RTN3 aggregation to tau pathology by recruiting PP2A B subunits and suppressing PP2A activity in a feedforward cycle.","evidence":"Interactome analysis, social-isolation AD mouse model, PP2A activity and tau phosphorylation assays, senktide disruption","pmids":["38011644"],"confidence":"Medium","gaps":["AI-assisted docking interactions not all biochemically validated","Trigger of presynaptic aggregation unresolved"]},{"year":2025,"claim":"Showed RTN3 controls CRTH2 levels differentially across cell types to restrain pulmonary fibrosis.","evidence":"RTN3-CRTH2 Co-IP, RTN3-null mice with bleomycin, fibroblast and macrophage studies, autophagy assays","pmids":["39972424"],"confidence":"Medium","gaps":["Mechanism of cell-type-specific CRTH2 regulation not fully defined","Single-lab study"]},{"year":2026,"claim":"Identified RTN3 as a promoter of DHCR7 ubiquitination, linking RTN3 loss to cholesterol-driven EGFR/ERK activation in cancer.","evidence":"RTN3-DHCR7 Co-IP, ubiquitination assay, EGFR/ERK pathway assays, simvastatin rescue","pmids":["41813657"],"confidence":"Medium","gaps":["Whether RTN3 itself is or recruits the E3 ligase unclear","Single-lab study"]},{"year":null,"claim":"How RTN3's many context-specific functions — ER-phagy, BACE1 regulation, lipid metabolism, antiviral signaling, and apoptosis — are coordinated by its oligomerization/aggregation state and topology in a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking monomer/aggregate state to the distinct downstream pathways","No high-resolution structure of RTN3 or its complexes","Signals that switch RTN3 between functions not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,14]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[12,16]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,8,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,16,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,24]}],"complexes":["RTN3-HSPA9-VDAC2 MAM complex","RTN3-RTN4 (Nogo-B) reticulon complex"],"partners":["BACE1","HSPA5","FADD","BCL-2","TRIM25","FABP5","DHCR7","BAP31"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95197","full_name":"Reticulon-3","aliases":["Homolog of ASY protein","HAP","Neuroendocrine-specific protein-like 2","NSP-like protein 2","Neuroendocrine-specific protein-like II","NSP-like protein II","NSPLII"],"length_aa":1032,"mass_kda":112.6,"function":"May be involved in membrane trafficking in the early secretory pathway. Inhibits BACE1 activity and amyloid precursor protein processing. May induce caspase-8 cascade and apoptosis. May favor BCL2 translocation to the mitochondria upon endoplasmic reticulum stress. Induces the formation of endoplasmic reticulum tubules (PubMed:25612671). Also acts as an inflammation-resolving regulator by interacting with both TRIM25 and RIGI, subsequently impairing RIGI 'Lys-63'-linked polyubiquitination leading to IRF3 and NF-kappa-B inhibition (Microbial infection) Plays a positive role in viral replication and pathogenesis of enteroviruses","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/O95197/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RTN3","classification":"Not 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autophagy receptor for ER-phagy of tubular ER. Oligomerization of the long isoform is sufficient to trigger fragmentation of ER tubules. The long N-terminal region of RTN3 contains multiple LC3-interacting regions (LIR motifs), and binding to LC3s/GABARAPs is essential for tubule fragmentation and lysosomal delivery. RTN3-mediated ER-phagy requires conventional autophagy components but is independent of FAM134B.\",\n      \"method\": \"Selective autophagy assays, LC3 co-immunoprecipitation, LIR motif identification/mutagenesis, live imaging, lysosomal delivery assays, genetic epistasis with FAM134B KO\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, mutagenesis of LIR motifs, live imaging, genetic epistasis), published in peer-reviewed journal, defines unique function among reticulon family members\",\n      \"pmids\": [\"28617241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RTN3 physically interacts with BACE1 via the transmembrane region of BACE1, and overexpression of RTN3 inhibits BACE1 activity, reducing Abeta40 and Abeta42 secretion by 30–50%. RTN3 also interacts with BACE2.\",\n      \"method\": \"Co-immunoprecipitation in SH-SY5Y and HEK293 cells, proteomic identification, BACE1 ectodomain deletion mutant binding assay, Abeta secretion assay\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in multiple cell lines, functional Abeta secretion assay, domain mapping with BACE1 truncation mutant, replicated by multiple subsequent studies\",\n      \"pmids\": [\"16965550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RTN3 adopts an omega-shaped membrane topology with two long transmembrane domains and both N- and C-termini facing the cytosolic side. The first transmembrane domain dictates membrane integration. Subtle alterations in this topology disrupt RTN3 binding to BACE1 and abolish its inhibitory effects on BACE1 activity.\",\n      \"method\": \"Membrane topology mapping assays, site-directed mutagenesis, co-immunoprecipitation, BACE1 activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct topology determination with mutagenesis linked to functional consequence (BACE1 binding and inhibition), multiple orthogonal approaches in single study\",\n      \"pmids\": [\"17699523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RTN3 deficiency in mice increases BACE1 protein levels and enhances APP processing at the beta-secretase site, leading to increased amyloid deposition in Alzheimer's mouse models. This demonstrates RTN3 negatively regulates BACE1 protein stability and activity in vivo.\",\n      \"method\": \"RTN3-null mouse generation, biochemical analysis of BACE1 levels and APP processing, histological analysis of amyloid deposition in RTN3-null x AD model mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse model with defined molecular phenotype (BACE1 levels, APP processing) and histological readout, replicated by in vivo AD model crossing\",\n      \"pmids\": [\"25319692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RTN3 overexpression reduces amyloid deposition in cortex and hippocampus of APP/PS1 mice, and this is associated with retention of BACE1 in the ER compartment where APP cleavage is less favored, altering BACE1 intracellular trafficking. RTN3 aggregates in dystrophic neurites offset this inhibitory effect.\",\n      \"method\": \"Triple transgenic mouse model (RTN3 overexpressor x APP/PS1), amyloid burden quantification, BACE1 intracellular localization studies, immunohistochemistry\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic mouse model with rigorous quantification, mechanistic link to BACE1 ER retention, complementary to RTN3-null findings\",\n      \"pmids\": [\"19625507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RTN3 (identified as ASYIP) forms a complex with ASY/Nogo-B (RTN4) in human cells; both hydrophobic transmembrane regions of RTN3 are required for this association. RTN3 co-localizes with ASY/Nogo-B in the ER, as shown by immunofluorescence. RTN3 contains a double-lysine ER retrieval motif at its C-terminus.\",\n      \"method\": \"Yeast two-hybrid cloning, co-immunoprecipitation in human cells, immunofluorescence co-localization, deletion/mutational analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and co-localization with mutational analysis in single lab; yeast two-hybrid corroborated by cell-based assays\",\n      \"pmids\": [\"12811824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RTN3 overexpression triggers ER overload response (EOR)-induced apoptosis through depletion of ER Ca2+ stores and sustained elevation of cytosolic Ca2+, activating caspase-12 and mitochondrial dysfunction. Overexpressed RTN3 also induces iNOS upregulation via Ca2+ release and reactive oxygen intermediates as a protective feedback.\",\n      \"method\": \"Overexpression in HeLa cells, Ca2+ measurement, caspase-12 activation assay, mitochondrial dysfunction assay, iNOS reporter/Western blot\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (Ca2+ flux, caspase activation, mitochondrial dysfunction) from single lab with overexpression model\",\n      \"pmids\": [\"15799019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Endogenous FADD is recruited by ER-bound RTN3 to the ER membrane, initiating caspase-8 cascade including Bid processing and cytochrome c release from mitochondria. Dominant-negative FADD (DD domain) abolishes these RTN3-mediated caspase-8 cascade events. Endogenous FADD is also recruited by endogenous RTN3 upon tunicamycin stimulation.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, dominant-negative FADD overexpression, caspase-8 activation assay, cytochrome c release assay, tunicamycin stimulation\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous Co-IP, functional epistasis with dominant-negative FADD, multiple caspase pathway readouts; single lab\",\n      \"pmids\": [\"17031492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RTN3 interacts with Bcl-2 on the ER membrane. Overexpressed Bcl-2 reduces RTN3-induced apoptosis. Increased endogenous RTN3 in the microsomal fraction (upon tunicamycin) enhances Bcl-2 localization to both microsomal and mitochondrial fractions, potentiating Bcl-2 anti-apoptotic activity.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, apoptosis assay, Bcl-2 stable overexpression in HeLa cells\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional consequence (Bcl-2 redistribution and anti-apoptotic effect), subcellular fractionation, single lab\",\n      \"pmids\": [\"17379544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RTN3 overexpression upregulates death receptor DR5 surface protein and downregulates c-FLIP, sensitizing cells to TRAIL-mediated apoptosis. DR5 siRNA or DR5/Fc chimera blocks RTN3-mediated TRAIL sensitization, establishing DR5 as the primary mediator. RTN3 also enhances TNF-alpha and Fas-mediated apoptosis.\",\n      \"method\": \"Stable RTN3 overexpression, DR5 siRNA knockdown, DR5/Fc chimera blocking, flow cytometry for DR4/DR5 surface levels, TRAIL apoptosis assay, c-FLIP Western blot\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis with DR5 siRNA and blocking chimera, multiple apoptosis readouts, single lab\",\n      \"pmids\": [\"19250737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RTN3 (CRELD1 binding partner) is recruited by CRELD1 interaction, which shifts RTN3 localization from the ER to the plasma membrane and moderately decreases RTN3-mediated apoptotic activity. CRELD1 interaction also partially suppresses tunicamycin-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation of ectopic and endogenous RTN3 with CRELD1, immunofluorescence localization, apoptosis assay\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and localization without full mechanistic follow-up; single lab\",\n      \"pmids\": [\"19521671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RTN3 expression is induced by cold/hypothermia and is a downstream effector of RBM3-mediated neuroprotection. RBM3 binds to RTN3 mRNA to drive increased RTN3 translation. RTN3 knockdown in mice eliminates cooling-induced neuroprotection; lentiviral RTN3 overexpression independently prevents synaptic loss and cognitive deficits in a mouse neurodegeneration model downstream of RBM3.\",\n      \"method\": \"Translatome profiling, RBM3 RNA-binding assay, RTN3 knockdown in mice (lentiviral), lentiviral RTN3 overexpression in mouse neurodegeneration model, cognitive/synaptic phenotyping\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo models (KD and OE), RBM3 binding assay, defined neuroprotective phenotype with mechanistic link; multiple orthogonal approaches\",\n      \"pmids\": [\"28238655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RTN3 interacts with HSPA5 (GRP78/BiP), and this interaction increases SREBP-1c and AMPK activity, promoting triglyceride biosynthesis and lipid droplet expansion. RTN3 transgenic mice develop obesity and hypertriglyceridemia; RTN3-null mice have reduced triglyceride accumulation.\",\n      \"method\": \"RTN3 transgenic and null mouse models, co-immunoprecipitation with HSPA5, SREBP-1c and AMPK activity assays, 3T3L1 cell culture, C. elegans genetic models\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with HSPA5, transgenic and null mouse phenotypes, in vitro cell culture; single lab, multiple model systems\",\n      \"pmids\": [\"29716941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BAP31 is a binding partner of RTN3 that stabilizes RTN3 monomer. BAP31 knockout in hippocampal neurons decreases RTN3 monomer availability, increases RTN3 aggregates, and consequently enhances BACE1-mediated APP processing and amyloid plaque formation.\",\n      \"method\": \"Co-immunoprecipitation of BAP31 and RTN3, conditional BAP31-KO mouse crossed with APP/PS1 AD model, primary hippocampal neuron culture, Western blot for RTN3 aggregates and BACE1 processing\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, conditional KO mouse with AD model crossing, mechanistic link to RTN3 stability and BACE1 processing; single lab\",\n      \"pmids\": [\"30596517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RTN3 is upregulated during RNA viral infection and acts as a negative regulator of RIG-I antiviral signaling. RTN3 aggregates on the ER and interacts with both TRIM25 and RIG-I, impairing K63-linked polyubiquitination of RIG-I, resulting in inhibition of IRF3 and NF-κB activation. RTN3 overexpression in mice reduces neutrophil infiltration and inflammatory damage upon VSV challenge.\",\n      \"method\": \"Co-immunoprecipitation of RTN3 with TRIM25 and RIG-I, ubiquitination assay (K63-linked), IRF3/NF-κB reporter assay, RTN3-overexpressing mouse model challenged with VSV, immunohistochemistry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with two partners (TRIM25 and RIG-I), direct ubiquitination assay, in vivo mouse model with defined inflammatory phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"34313226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RTN3 deficiency in kidney proximal tubular epithelial cells activates the IGF2-JAK2-STAT3 pathway through interaction with GPBP1, leading to collagen biosynthesis upregulation and mitochondrial dysfunction, phenocopying chronic kidney disease and fibrosis.\",\n      \"method\": \"RTN3-null mouse model, co-immunoprecipitation with GPBP1, IGF2-JAK2-STAT3 pathway analysis, primary proximal tubular epithelial cells, HEK293 cells in vitro\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model, Co-IP with GPBP1, pathway activation assays; single lab\",\n      \"pmids\": [\"35596061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RTN3 directly binds FABP5 to facilitate directed transport of fatty acids to the ER, promoting lipid droplet biogenesis in a DGAT2-dependent manner in cardiomyocytes. Lipid overload-induced RTN3 upregulation is driven by C/EBPα, which binds the RTN3 promoter.\",\n      \"method\": \"Co-immunoprecipitation of RTN3 and FABP5, gain/loss-of-function in cardiomyocytes, DGAT2 inhibition, C/EBPα promoter binding assay (ChIP), HFD mouse model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct Co-IP, DGAT2 epistasis, ChIP for transcriptional regulation; multiple methods in single lab\",\n      \"pmids\": [\"38017147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RTN3 interacts with GRP78 (HSPA5) in hepatocytes, and increased RTN3 inhibits the AMPK-IDH2 pathway, leading to mitochondrial dysfunction and lipid accumulation phenocopying NAFLD. RTN3 knockout relieves fatty liver and mitochondrial dysfunction.\",\n      \"method\": \"Co-immunoprecipitation with GRP78, AMPK and IDH2 activity assays, RTN3-null mouse model, primary hepatocytes, L02 cell line, C. elegans strain, HFD model\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with GRP78, pathway activity assays, KO mouse and multiple cell models; single lab\",\n      \"pmids\": [\"36925557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RTN3 deficiency disrupts the RTN3-HSPA9-VDAC2 complex at mitochondria-associated membranes (MAMs), impairing ER-mitochondrion contact and causing mitochondrial dysfunction that exacerbates cisplatin-induced acute kidney injury.\",\n      \"method\": \"Co-immunoprecipitation of RTN3, HSPA9, and VDAC2, RTN3-null mouse model with cisplatin treatment, primary renal tubular epithelial cells, HK2 cell line, MAM analysis\",\n      \"journal\": \"Mitochondrion\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of three-protein complex, KO mouse with defined phenotype; single lab\",\n      \"pmids\": [\"38336146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In socially isolated AD mice, RTN3 aggregates in presynaptic regions and disturbs mossy fibre bouton formation by recruiting multiple mitochondrial and vesicle-related proteins. RTN3 aggregation also recruits PP2A B subunits, suppressing PP2A activity and inducing tau hyperphosphorylation, which further elevates RTN3 in a feedforward cycle.\",\n      \"method\": \"RTN3 interactome analysis (AI-assisted molecular docking), in vivo mouse model (social isolation + AD), PP2A activity assay, tau phosphorylation analysis, senktide treatment to disrupt RTN3 interactions\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with defined synaptic and tau phenotypes, PP2A activity assay, interactome analysis; single lab with multiple readouts\",\n      \"pmids\": [\"38011644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RTN3 interacts with CRTH2 in lung fibroblasts; RTN3 deficiency reduces ER-anchored CRTH2 (which antagonizes collagen biosynthesis) and simultaneously reduces autophagy-mediated degradation of CRTH2 in macrophages (where CRTH2 activates profibrotic differentiation), resulting in aggravated pulmonary fibrosis.\",\n      \"method\": \"Co-immunoprecipitation of RTN3 and CRTH2, RTN3-null mouse model with bleomycin treatment, lung fibroblast and alveolar macrophage studies, autophagy assay\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KO mouse with fibrosis phenotype, mechanistic dissection in two cell types; single lab\",\n      \"pmids\": [\"39972424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RTN3 interacts with Ras at the ER, as demonstrated by confocal co-localization and co-immunoprecipitation. RTN3 upregulation during HSV mutant infection correlates with decreased Ras on the plasma membrane.\",\n      \"method\": \"Confocal co-localization, co-immunoprecipitation, siRNA knockdown of RTN3, Western blot and flow cytometry for Ras distribution\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and co-localization, correlative context, single lab\",\n      \"pmids\": [\"17218780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RTN3 directly interacts with DHCR7 and promotes its ubiquitination. RTN3 downregulation stabilizes DHCR7, elevating cholesterol concentration and activating the EGFR/ERK pathway in thyroid cancer.\",\n      \"method\": \"Co-immunoprecipitation of RTN3 and DHCR7, ubiquitination assay, RTN3 loss-of-function experiments, EGFR/ERK pathway activity assay, Simvastatin rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, direct ubiquitination assay, pathway rescue with statin; single lab\",\n      \"pmids\": [\"41813657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RTN3 and RTN4 are required for the formation of SARS-CoV-2 replication organelles through direct interaction with viral proteins NSP3 and NSP4.\",\n      \"method\": \"Co-immunoprecipitation/interaction studies with viral NSP3/NSP4, RTN3/RTN4 loss-of-function, replication organelle formation assay (as described by Williams et al., cited in this commentary)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction with viral proteins, functional replication organelle assay (per cited primary study); this entry is a commentary citing the primary research\",\n      \"pmids\": [\"37318453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RTN3 variant T39M (c.116C>T) found in early-onset AD patients causes impaired axonal transport of BACE1 when overexpressed in cultured neurons. The c.-8G>T 5'-UTR variant reduces RTN3 expression.\",\n      \"method\": \"Luciferase reporter assay for expression, kymograph analysis of BACE1-RFP particle mobility in neurons transfected with WT or variant RTN3\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging (kymography) of BACE1 transport, reporter assay for expression; single lab, disease-variant functional characterization\",\n      \"pmids\": [\"29356939\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RTN3 is an ER-resident reticulon protein with an omega-shaped transmembrane topology that serves multiple mechanistic roles: (1) as a selective ER-phagy receptor for tubular ER degradation via LIR-motif-dependent interaction with LC3s/GABARAPs; (2) as a negative regulator of BACE1 activity through direct transmembrane interaction, retaining BACE1 in the ER and reducing amyloid-beta production; (3) as a modulator of lipid metabolism through interactions with HSPA5/GRP78, FABP5, and DHCR7; (4) as a negative regulator of RIG-I antiviral signaling by impairing TRIM25-mediated K63 ubiquitination; and (5) as an ER-based scaffold that recruits apoptotic machinery (FADD/caspase-8) and interacts with Bcl-2, PP2A, and multiple other partners to modulate cell survival, mitochondrial function, and ER stress responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RTN3 is an ER-resident reticulon protein that shapes tubular ER and acts as a multifunctional regulator of membrane dynamics, lipid metabolism, and cell-fate signaling [#0, #2]. It adopts an omega-shaped membrane topology with two long transmembrane domains and cytosolically exposed N- and C-termini, a configuration whose integrity is required for its protein interactions [#2]. The full-length long isoform functions as a selective ER-phagy receptor: its oligomerization fragments ER tubules, and multiple N-terminal LIR motifs bind LC3s/GABARAPs to deliver tubular ER to lysosomes through conventional autophagy machinery independently of FAM134B [#0]. RTN3 is a direct negative regulator of the beta-secretase BACE1, binding it via the BACE1 transmembrane region, retaining it in the ER where APP cleavage is disfavored, and limiting amyloid-beta production; loss of RTN3 raises BACE1 levels and amyloid deposition in vivo while its overexpression reduces amyloid burden [#1, #3, #4]. RTN3 modulates lipid homeostasis through interactions with HSPA5/GRP78, FABP5, and DHCR7, influencing triglyceride and lipid-droplet biogenesis and cholesterol/EGFR signaling [#12, #16, #22]. It additionally restrains RIG-I antiviral signaling by impairing TRIM25-mediated K63-linked ubiquitination of RIG-I [#14], and serves as an ER scaffold that recruits apoptotic machinery and partners including FADD/caspase-8 and Bcl-2 to tune cell survival and ER stress responses [#7, #8]. A neuroprotective role downstream of cold-induced RBM3 has also been established in vivo [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that RTN3 partners with another reticulon and resides in the ER, defining its baseline membrane localization and self-association behavior.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, immunofluorescence co-localization with ASY/Nogo-B (RTN4) in human cells\",\n      \"pmids\": [\"12811824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the RTN3-RTN4 complex not defined\", \"ER retrieval motif role not tested for trafficking\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that excess RTN3 can drive ER-stress apoptosis, raising the question of how an ER-shaping protein controls cell fate.\",\n      \"evidence\": \"Overexpression in HeLa cells with Ca2+ flux, caspase-12 activation, and mitochondrial dysfunction readouts\",\n      \"pmids\": [\"15799019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression model may not reflect endogenous signaling\", \"Direct effectors of the ER overload response not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified RTN3 as a direct binding partner and negative regulator of BACE1, linking it to amyloid-beta production.\",\n      \"evidence\": \"Reciprocal Co-IP in SH-SY5Y/HEK293, BACE1 ectodomain deletion mapping, Abeta secretion assay\",\n      \"pmids\": [\"16965550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous stoichiometry of the interaction unknown\", \"Mechanism of activity inhibition vs. trafficking control not separated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected ER-bound RTN3 to extrinsic apoptotic signaling by showing it recruits FADD and triggers a caspase-8 cascade.\",\n      \"evidence\": \"Endogenous Co-IP, dominant-negative FADD epistasis, caspase-8/cytochrome c assays under tunicamycin\",\n      \"pmids\": [\"17031492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent replication\", \"How an ER-resident protein engages canonical death-receptor adaptors mechanistically unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the omega-shaped topology of RTN3 and tied it directly to BACE1 binding, providing the structural basis for its inhibitory function.\",\n      \"evidence\": \"Membrane topology mapping plus site-directed mutagenesis linked to BACE1 binding and activity\",\n      \"pmids\": [\"17699523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure not determined\", \"Oligomerization geometry not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended RTN3's apoptotic role by showing it interacts with Bcl-2 and redistributes it, integrating pro- and anti-apoptotic balance at the ER.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, Bcl-2 overexpression apoptosis assays in HeLa\",\n      \"pmids\": [\"17379544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"Relationship to FADD-driven pathway unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated in vivo that RTN3 overexpression retains BACE1 in the ER and lowers amyloid burden, establishing trafficking control as a mechanism.\",\n      \"evidence\": \"RTN3 x APP/PS1 transgenic mice with amyloid quantification and BACE1 localization studies\",\n      \"pmids\": [\"19625507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effect of RTN3 aggregates that offset inhibition not fully mechanistically dissected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked RTN3 to death-receptor sensitization by showing it upregulates DR5 and downregulates c-FLIP.\",\n      \"evidence\": \"Stable overexpression, DR5 siRNA and DR5/Fc blocking, TRAIL apoptosis assays\",\n      \"pmids\": [\"19250737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional vs. post-translational basis of DR5 upregulation unknown\", \"Single-lab overexpression study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided loss-of-function genetic proof that RTN3 negatively regulates BACE1 stability and amyloid deposition in vivo.\",\n      \"evidence\": \"RTN3-null mice and crosses to AD models with BACE1/APP processing biochemistry and histology\",\n      \"pmids\": [\"25319692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for BACE1 protein stabilization on RTN3 loss not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined RTN3 as a selective ER-phagy receptor, assigning it a distinct catabolic function within the reticulon family.\",\n      \"evidence\": \"Selective autophagy assays, LIR-motif mutagenesis, LC3 Co-IP, live imaging, FAM134B-KO epistasis\",\n      \"pmids\": [\"28617241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal triggering RTN3 oligomerization/activation unknown\", \"Cargo selectivity determinants not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed RTN3 downstream of cold-induced RBM3 as a translationally regulated neuroprotective effector.\",\n      \"evidence\": \"Translatome profiling, RBM3 RNA-binding assay, RTN3 knockdown and lentiviral overexpression in mouse neurodegeneration models\",\n      \"pmids\": [\"28238655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which RTN3 prevents synaptic loss not resolved\", \"Relation to ER-phagy or BACE1 functions unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected RTN3 to lipid metabolism through HSPA5 binding driving triglyceride biosynthesis and lipid-droplet expansion.\",\n      \"evidence\": \"RTN3 transgenic and null mice, HSPA5 Co-IP, SREBP-1c/AMPK assays, 3T3L1 and C. elegans models\",\n      \"pmids\": [\"29716941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanistic step from HSPA5 binding to SREBP-1c activation not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified BAP31 as a stabilizer of the RTN3 monomer, linking RTN3 aggregation state to BACE1-driven amyloid processing.\",\n      \"evidence\": \"Co-IP, conditional BAP31-KO mice crossed with APP/PS1, hippocampal neuron culture\",\n      \"pmids\": [\"30596517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why monomer vs. aggregate differentially regulates BACE1 not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked an RTN3 coding variant and reduced expression to early-onset AD by impairing BACE1 axonal transport.\",\n      \"evidence\": \"Luciferase reporter for 5'-UTR variant and kymography of BACE1-RFP mobility in neurons\",\n      \"pmids\": [\"29356939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathogenicity of T39M not established beyond cell-based assays\", \"No family co-segregation data in the timeline\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established RTN3 as a negative regulator of innate antiviral signaling by impairing TRIM25-mediated K63 ubiquitination of RIG-I.\",\n      \"evidence\": \"Co-IP with TRIM25 and RIG-I, K63-linked ubiquitination assay, IRF3/NF-kB reporters, VSV challenge in RTN3-overexpressing mice\",\n      \"pmids\": [\"34313226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RTN3 aggregation sequesters the TRIM25/RIG-I complex structurally unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RTN3 deficiency drives renal fibrosis via GPBP1 interaction and IGF2-JAK2-STAT3 activation.\",\n      \"evidence\": \"RTN3-null mice, GPBP1 Co-IP, pathway analysis in proximal tubular cells\",\n      \"pmids\": [\"35596061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect of RTN3 on GPBP1 function not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended RTN3's lipid role to cardiomyocytes by direct FABP5 binding driving fatty-acid delivery and DGAT2-dependent lipid-droplet biogenesis.\",\n      \"evidence\": \"RTN3-FABP5 Co-IP, gain/loss-of-function, DGAT2 inhibition, C/EBPalpha ChIP, HFD mice\",\n      \"pmids\": [\"38017147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FABP5 transport mechanism generalizes beyond cardiomyocytes untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated RTN3-GRP78 interaction in hepatic mitochondrial dysfunction and steatosis via AMPK-IDH2 suppression.\",\n      \"evidence\": \"GRP78 Co-IP, AMPK/IDH2 assays, RTN3-null mice, hepatocyte/L02/C. elegans models\",\n      \"pmids\": [\"36925557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship to the HSPA5-SREBP-1c lipid axis not reconciled\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed RTN3 (with RTN4) is co-opted by SARS-CoV-2 to build replication organelles via NSP3/NSP4 interaction.\",\n      \"evidence\": \"Interaction studies with viral NSP3/NSP4 and replication organelle formation assay (commentary citing primary study)\",\n      \"pmids\": [\"37318453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Entry is a commentary; primary mechanistic detail limited\", \"Specific RTN3 contribution vs. RTN4 not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an RTN3-HSPA9-VDAC2 complex at MAMs mediating ER-mitochondrion contact and protecting against kidney injury.\",\n      \"evidence\": \"Three-protein Co-IP, RTN3-null mice with cisplatin, MAM analysis in renal tubular cells\",\n      \"pmids\": [\"38336146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and assembly order of the complex unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked RTN3 aggregation to tau pathology by recruiting PP2A B subunits and suppressing PP2A activity in a feedforward cycle.\",\n      \"evidence\": \"Interactome analysis, social-isolation AD mouse model, PP2A activity and tau phosphorylation assays, senktide disruption\",\n      \"pmids\": [\"38011644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AI-assisted docking interactions not all biochemically validated\", \"Trigger of presynaptic aggregation unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed RTN3 controls CRTH2 levels differentially across cell types to restrain pulmonary fibrosis.\",\n      \"evidence\": \"RTN3-CRTH2 Co-IP, RTN3-null mice with bleomycin, fibroblast and macrophage studies, autophagy assays\",\n      \"pmids\": [\"39972424\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of cell-type-specific CRTH2 regulation not fully defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified RTN3 as a promoter of DHCR7 ubiquitination, linking RTN3 loss to cholesterol-driven EGFR/ERK activation in cancer.\",\n      \"evidence\": \"RTN3-DHCR7 Co-IP, ubiquitination assay, EGFR/ERK pathway assays, simvastatin rescue\",\n      \"pmids\": [\"41813657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RTN3 itself is or recruits the E3 ligase unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RTN3's many context-specific functions — ER-phagy, BACE1 regulation, lipid metabolism, antiviral signaling, and apoptosis — are coordinated by its oligomerization/aggregation state and topology in a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking monomer/aggregate state to the distinct downstream pathways\", \"No high-resolution structure of RTN3 or its complexes\", \"Signals that switch RTN3 between functions not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 14]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [12, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0005789\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 8, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 16, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 24]}\n    ],\n    \"complexes\": [\n      \"RTN3-HSPA9-VDAC2 MAM complex\",\n      \"RTN3-RTN4 (Nogo-B) reticulon complex\"\n    ],\n    \"partners\": [\n      \"BACE1\",\n      \"HSPA5\",\n      \"FADD\",\n      \"Bcl-2\",\n      \"TRIM25\",\n      \"FABP5\",\n      \"DHCR7\",\n      \"BAP31\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}