{"gene":"DRAM1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2006,"finding":"DRAM1 (DRAM) is a direct transcriptional target of p53 that encodes a lysosomal protein; p53 induces autophagy in a DRAM-dependent manner, and DRAM is essential for p53-mediated apoptosis.","method":"RNAi knockdown, overexpression, lysosomal localization by cell fractionation/imaging, p53-dependent induction assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA knockdown, overexpression, subcellular fractionation, genetic epistasis with p53), replicated across subsequent independent studies","pmids":["16839881"],"is_preprint":false},{"year":2007,"finding":"TA-p73 transcriptionally regulates DRAM but, unlike p53, p73's induction of autophagy is DRAM-independent; deltaN-p73 negatively regulates p53-induced and p73-induced autophagy but not starvation-induced autophagy.","method":"RNAi knockdown of DRAM, overexpression of p73 isoforms, autophagy flux assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal RNAi and OE in one lab, two orthogonal methods, single lab","pmids":["17304243"],"is_preprint":false},{"year":2007,"finding":"FLJ11259/DRAM1 is a direct p53 target gene with a functional p53 response element 22.3 kb upstream of the first coding exon; p53 binds this element in vivo (ChIP), and binding is enhanced after cisplatin treatment. The protein contains six transmembrane domains and localizes in a punctate cytoplasmic pattern.","method":"p53 siRNA knockdown, isogenic p53+/+ vs p53-suppressed cell lines, luciferase reporter assay, chromatin immunoprecipitation, GFP-fusion confocal microscopy","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP confirming direct p53 binding, reporter assay, siRNA validation, multiple orthogonal methods in one study","pmids":["17397945"],"is_preprint":false},{"year":2009,"finding":"DRAM1 is a lysosomal protein; a closely related paralogue DRAM2 (45% identity) also localizes to lysosomes but does not modulate autophagy on overexpression and is not induced by p53 or p73. Drosophila DmDRAM, the single fly orthologue, retains the ability to modulate autophagy.","method":"Overexpression with subcellular localization (immunofluorescence), autophagy flux assays, comparison of p53/p73 induction across paralogues","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — localization and functional assays with overexpression, single lab, two orthogonal readouts","pmids":["19556885"],"is_preprint":false},{"year":2009,"finding":"JNK activation is required upstream of DRAM induction by 2-methoxyestradiol; JNK promotes DRAM expression in a p53-partially-regulated manner, and DRAM silencing reduces both autophagy and apoptosis triggered by 2-ME.","method":"siRNA knockdown of DRAM and JNK, pharmacological JNK inhibition, autophagy/apoptosis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with dual functional readouts (autophagy and apoptosis), single lab","pmids":["19706754"],"is_preprint":false},{"year":2012,"finding":"DRAM1 promotes autophagy flux by enhancing lysosomal acidification (V-ATPase activity), promoting autophagosome-lysosome fusion, and activating lysosomal cathepsin D; siRNA knockdown of DRAM1 reduces lysosomal V-ATPase activity and slows clearance of autophagosomes.","method":"siRNA knockdown, RFP-LC3 flux assay, lysosomal pH measurement, cathepsin D activity assay, rapamycin washout experiment","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (flux, pH, cathepsin activity, autophagosome clearance) in one study, single lab","pmids":["23696801"],"is_preprint":false},{"year":2012,"finding":"DRAM1 regulates p62 localization to autophagosomes and its autophagy-mediated degradation; DRAM1 knockdown decreases this process. DRAM1 and p62 cooperatively regulate cell motility and invasion in glioblastoma stem cells, associated with reduced ATP and lactate levels. Starvation- or mTOR/PI3K inhibition-induced autophagy is not affected by DRAM1 or p62 knockdown.","method":"siRNA knockdown, immunofluorescence localization of p62, invasion/migration assays, metabolic measurements","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA knockdown with functional (invasion) and biochemical (p62 localization, metabolism) readouts, single lab","pmids":["22525272"],"is_preprint":false},{"year":2012,"finding":"DRAM-1 encodes multiple p53-inducible splice variants (SV1, SV4, SV5); SV1 localizes to lysosomes/endosomes, SV4 partially localizes to peroxisomes and ER, SV5 partially localizes to autophagosomes and ER. SV4 and SV5 modulate autophagy without inducing programmed cell death.","method":"Cloning of splice variants, immunofluorescence co-localization with organelle markers, autophagy assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct subcellular localization experiments with multiple organelle markers, autophagy functional assay, single lab","pmids":["22082963"],"is_preprint":false},{"year":2013,"finding":"DRAM1 interacts directly with BAX protein, inhibiting BAX degradation by autophagy, thereby increasing BAX protein levels in a transcription-independent manner. DRAM1 recruits BAX to lysosomes, triggering lysosomal cathepsin B release and BID cleavage, leading to mitochondrial cytochrome c release and caspase-3 activation.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, BAX half-life measurement, cathepsin B/cytochrome c release assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — co-IP demonstrating direct DRAM1-BAX interaction, multiple downstream functional assays, half-life measurement, single lab with multiple orthogonal methods","pmids":["25633293"],"is_preprint":false},{"year":2013,"finding":"HIV infection induces DRAM expression in a p53-dependent manner in CD4+ T cells; DRAM knockdown inhibits autophagy and lysosomal membrane permeabilization (LMP), cytochrome C release, MOMP, and cell death, but increases viral production.","method":"siRNA knockdown of DRAM and p53, LMP assay, cytochrome C release, MOMP measurement, viral titer","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple functional readouts (LMP, MOMP, viral replication), single lab","pmids":["23658518"],"is_preprint":false},{"year":2014,"finding":"DRAM1 expression is induced downstream of the TLR/IL1R-MYD88-NF-κB innate immune sensing pathway in response to mycobacterial infection; DRAM1 activates selective autophagy against mycobacteria in a p53-independent manner requiring STING and p62/SQSTM1.","method":"MYD88/NF-κB inhibition, siRNA knockdown of DRAM1, overexpression, co-localization with Mtb, zebrafish and human macrophage infection models","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (MYD88, NF-κB, STING, p62 knockdowns), reciprocal gain- and loss-of-function, replicated in two model systems (zebrafish and human macrophages)","pmids":["24922577"],"is_preprint":false},{"year":2014,"finding":"Phosphorylated AKT (p-AKT) binds DRAM in the cytoplasm, blocking DRAM translocation to mitochondria; inactivation of PI3K/AKT pathway rescues DRAM translocation to mitochondria, where DRAM induces mitophagy and apoptosis in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation of p-AKT and DRAM, immunofluorescence tracking of DRAM localization, PI3K inhibition, siRNA knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating p-AKT/DRAM interaction, localization assay with functional consequence, single lab","pmids":["24556693"],"is_preprint":false},{"year":2015,"finding":"DRAM-3 (TMEM150B), a DRAM1-related protein, localizes to lysosomes/autolysosomes, endosomes, and plasma membrane; it modulates autophagy flux and promotes cell survival under glucose deprivation in an autophagy-independent manner.","method":"Immunofluorescence localization, CRISPR/Cas9 disruption, autophagy flux assays, clonogenic survival assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knockout confirming endogenous role, localization, flux assays, single lab","pmids":["25929859"],"is_preprint":false},{"year":2018,"finding":"Dram1 is required for genotoxic stress-induced alternative (Atg5-independent) autophagy; Dram1 functions in the closure of isolation membranes downstream of p53 in this alternative autophagy pathway.","method":"Dram1 overexpression/knockdown in cells with or without Atg5, electron microscopy of isolation membranes, epistasis with p53","journal":"Cell stress","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with Atg5 and p53, morphological EM analysis, single lab","pmids":["31225467"],"is_preprint":false},{"year":2018,"finding":"DRAM1 interacts with Atg7 (but not directly with Atg5 or Atg12), promoting formation of the Atg12-Atg5 conjugate; DRAM1 overexpression restores autophagic flux and autophagosome-to-autophagolysosome conversion in ischemic cardiomyocytes. Atg7 siRNA abolishes these effects.","method":"Co-immunoprecipitation (DRAM1 with Atg7, Atg5, Atg12), mRFP-GFP-LC3 flux assay, siRNA knockdown, adenoviral overexpression in rat AMI model","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with negative controls (no Atg5/Atg12 interaction), flux assay, genetic rescue, single lab","pmids":["30144448"],"is_preprint":false},{"year":2019,"finding":"DRAM1 binds the membrane carrier protein SCAMP3 and amino acid transporters SLC1A5 and LAT1, directing them to lysosomes to permit efficient efflux of amino acids from lysosomes into the cytoplasm, which is required for mTORC1 activation. Loss of DRAM1 impairs mTORC1 activation, insulin signaling, glycemic balance, and adipocyte differentiation. This effect is autophagy-independent.","method":"Co-immunoprecipitation, lysosomal fractionation, amino acid efflux assays, DRAM-1 knockout mouse, mTORC1 activity measurements, adipocyte differentiation assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple binding partners identified by co-IP, lysosomal fractionation, in vivo knockout mouse, multiple functional readouts across cell types and tissues, single lab with multiple orthogonal methods","pmids":["31492633"],"is_preprint":false},{"year":2019,"finding":"DRAM1 inhibits rpS6 phosphorylation in an mTORC1-dependent manner and inhibits activation of the PI3K-Akt pathway stimulated by growth factors; DRAM1 localizes at the plasma membrane and regulates phosphorylation of the IGF-1 receptor.","method":"FLAG-DRAM1 overexpression, siRNA knockdown, Western blot for phospho-rpS6/Akt/IGF-1R, immunostaining for DRAM1 localization, CCK-8 and colony formation assays","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — overexpression and knockdown with pathway activity readouts, localization data, single lab","pmids":["30902093"],"is_preprint":false},{"year":2019,"finding":"DRAM1 deficiency causes fragmentation of the Golgi apparatus; DRAM1 is partially localized in the Golgi, and its knockdown delays ER-to-plasma membrane transport of VSVG-GFP and impedes retrograde trafficking of CI-MPR from plasma membrane to Golgi.","method":"siRNA knockdown, immunofluorescence with Golgi markers, ts045-VSVG-GFP transport assay, CI-MPR trafficking assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — knockdown with functional vesicular transport readouts and localization data, single lab","pmids":["31356858"],"is_preprint":false},{"year":2020,"finding":"Dram1 deficiency in zebrafish reduces phagosome/vesicle acidification of Mycobacterium marinum-containing vesicles, impairs autophagic targeting of Mm, and leads to premature pyroptotic death of infected macrophages via caspase a/gasdermin Eb; knockdown of caspa and gsdmeb reverts the increased bacterial burden.","method":"Zebrafish dram1 CRISPR mutant, in vivo imaging of autophagic targeting, LysoTracker acidification assay, caspa/gsdmeb knockdown epistasis, RNA-seq","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR knockout, in vivo imaging, genetic epistasis with pyroptosis effectors, multiple readouts in vivo","pmids":["32332700"],"is_preprint":false},{"year":2020,"finding":"DRAM1 interacts with EPS15 to promote EGFR endocytosis, and recruits V-ATPase (V-ATP6V1 subunit) to lysosomes, increasing lysosomal V-ATPase assembly, lowering lysosomal pH, and activating lysosomal proteases, resulting in accelerated EGFR lysosomal degradation and suppression of EGFR signaling.","method":"Proximity labeling (BioID) followed by proteomics, co-IP of DRAM1 with EPS15, lysosomal pH measurement, EGFR degradation assay, xenograft tumor model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — proximity labeling proteomics plus co-IP validation, lysosomal pH measurement, EGFR trafficking assay, in vivo xenograft, single lab with multiple orthogonal methods","pmids":["32943616"],"is_preprint":false},{"year":2021,"finding":"DRAM interacts with stomatin (STOM) and promotes its lysosomal localization; fatty acid-induced DRAM enhances lysosomal membrane permeabilization (LMP) and promotes exosome secretion from hepatocytes. DRAM knockout reverses high-fat diet-induced increase in exosome secretion.","method":"Co-immunoprecipitation of DRAM and STOM, DRAM knockout mouse model, siRNA knockdown, LMP assay, exosome quantification","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, DRAM KO mouse, siRNA with functional exosome readout, single lab","pmids":["34731006"],"is_preprint":false},{"year":2021,"finding":"DRAM1 interacts with PKM2 and increases PKM2 levels at the plasma membrane; ethanol-induced DRAM1 in hepatocytes increases secretion of PKM2-enriched extracellular vesicles/ectosomes that promote macrophage M1 activation.","method":"Co-immunoprecipitation of DRAM1 and PKM2, DRAM1 knockout and liver-specific overexpression mouse models, ectosome isolation, macrophage activation assay","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, in vivo KO and OE mouse models, functional macrophage activation readout, single lab","pmids":["35036051"],"is_preprint":false},{"year":2024,"finding":"DRAM1 interacts with STIM1 to tether lysosomes to the ER, perturbing STIM1 function in maintaining intracellular calcium homeostasis; excess DRAM1 disrupts ER structure, triggers ER stress, and induces protective ER-phagy. Lysosomal localization of DRAM1 requires its intact cytosol-facing C-terminal domain. STIM1 overexpression restores calcium homeostasis, ER stress response, and AMPK-ULK1 signaling in cells with excess DRAM1.","method":"Co-immunoprecipitation of DRAM1 and STIM1, calcium imaging, ER morphology analysis, ER-phagy assay, AMPK-ULK1 signaling readouts, domain-deletion mutants for localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — co-IP, domain mutagenesis for localization, calcium homeostasis assay, ER-phagy, genetic rescue with STIM1 OE, multiple orthogonal methods in one study","pmids":["39292746"],"is_preprint":false},{"year":2023,"finding":"In macrophages, DRAM1 localizes to mycobacteria-containing vesicles post-phagocytosis; DRAM1 knockdown reduces LC3 recruitment to mycobacteria and acidification of mycobacteria-containing vesicles, and reduces fusion with LAMP1-positive lysosomes, impairing intracellular killing.","method":"DRAM1 siRNA knockdown in RAW264.7 macrophages, immunofluorescence co-localization with LC3/LysoTracker/LAMP1, bacterial survival assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA with multiple localization and functional readouts, single lab","pmids":["36980169"],"is_preprint":false},{"year":2024,"finding":"DRAM1 and xenophagy receptors Optn and p62 independently promote host defense against Mycobacterium marinum; Dram1 overexpression can compensate for loss of Optn or p62, and vice versa. Dram1 overexpression restores Lc3-Mm interaction in optn/p62 double mutants, indicating Dram1-mediated defense does not rely on specific xenophagy receptors.","method":"Single and double knockout zebrafish lines, overexpression rescue experiments, Lc3-Mm co-localization imaging, bacterial burden quantification","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis using KO/OE in zebrafish, co-localization readout, single lab","pmids":["38264729"],"is_preprint":false},{"year":2025,"finding":"DRAM1 directly binds VAMP8 on lysosomes; this interaction is enhanced upon autophagy induction. DRAM1 competitively inhibits CHIP/STUB1-mediated ubiquitination of VAMP8 at Lys68, Lys72, and Lys75, stabilizing lysosomal VAMP8 and promoting assembly of the STX17-SNAP29-VAMP8 SNARE complex, thereby facilitating autophagosome-lysosome fusion and autophagic flux. DRAM1-mediated VAMP8 stabilization promotes HCC cell extravasation.","method":"Co-immunoprecipitation of DRAM1-VAMP8 and STUB1-VAMP8, ubiquitination assay, site-directed mutagenesis of VAMP8 lysines, SNARE complex assembly assay, ATG5/ATG7 knockout, mouse and zebrafish metastasis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-IP, site-directed mutagenesis identifying ubiquitination sites, SNARE assembly assay, genetic rescue with ATG5/ATG7 KO, replicated in mouse and zebrafish in vivo models","pmids":["40595569"],"is_preprint":false},{"year":2025,"finding":"DRAM1 activates AMPK and mediates pro-senescent autophagy (DMPA) in response to aging-associated metabolic cues (N-acetylhistamine, phosphatidylethanolamine); DRAM1-mediated autophagy in this context does not notably degrade SQSTM1/p62, distinguishing it from general macroautophagy.","method":"DRAM1 overexpression/knockdown in human MSCs and mouse hepatocytes, metabolomics, AMPK activity assay, autophagy flux assay, senescence markers, N-AcHA and ethanolamine supplementation","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — DRAM1 manipulation with AMPK activity and senescence readouts, metabolomics correlation, single lab","pmids":["41037659"],"is_preprint":false},{"year":2023,"finding":"Dram1/DRAM1 promotes LC3-associated phagocytosis (LAP) of Salmonella Typhimurium; Dram1 knockdown or mutation reduces GFP-Lc3 association with Salmonella and abolishes phagosomal NADPH oxidase-dependent ROS response to the bacteria. These results were confirmed in zebrafish and murine RAW264.7 macrophages.","method":"Morpholino knockdown, CRISPR mutation, mRNA overexpression in zebrafish, Salmonella ROS biosensor, GFP-Lc3 imaging, siRNA in RAW264.7 macrophages","journal":"Autophagy reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in two model systems with ROS biosensor and LC3 imaging readouts, single lab","pmids":["40950712"],"is_preprint":false},{"year":2012,"finding":"p73-regulated DRAM-1 is functionally required for neutrophil differentiation of APL cells; DRAM-1 expression is induced during ATRA-induced differentiation of NB4 APL cells, and its knockdown impairs this differentiation. p73 inhibition prevents both differentiation and DRAM-1 induction.","method":"siRNA knockdown of DRAM-1, ATRA differentiation assay, p73 inhibition, DRAM-1 expression measurement by qPCR/Western blot","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — siRNA knockdown with differentiation phenotype and p73 epistasis, single lab","pmids":["22981223"],"is_preprint":false},{"year":2012,"finding":"Serum deprivation induces DRAM expression in liver cancer cells through epigenetic remodeling: active chromatin marks (diacetyl-H3, tetra-acetyl-H4, trimethyl-H3K4) increase and repressive mark (dimethyl-H3K9) decreases at the DRAM core promoter. The chromatin remodeling factor Brg-1 is enriched at the DRAM promoter and is required for serum deprivation-induced DRAM expression.","method":"ChIP for histone marks and Brg-1 at DRAM promoter, Brg-1 knockdown, luciferase reporter for DRAM promoter activity","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with multiple histone marks plus functional Brg-1 knockdown, single lab","pmids":["23251372"],"is_preprint":false},{"year":2025,"finding":"DRAM1 interacts with VAMP8; this interaction is enhanced by autophagy stimulation. DRAM1 preferentially promotes autophagosome-lysosome fusion by enhancing assembly of the STX17-SNAP29-VAMP8 SNARE complex, and inhibits VAMP8 ubiquitination at Lys68, Lys72, and Lys75 by competing with CHIP/STUB1.","method":"Co-immunoprecipitation, ubiquitination assay, mutagenesis of VAMP8 lysine residues, SNARE complex co-IP, autophagy flux assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — co-IP, site-directed mutagenesis, SNARE complex assembly assay, ubiquitination assay, corroborates PMID:40595569 from same group","pmids":["40884094"],"is_preprint":false}],"current_model":"DRAM1 is a multi-pass lysosomal transmembrane protein and direct transcriptional target of p53 that regulates autophagy flux by promoting lysosomal acidification (via V-ATPase assembly), facilitating autophagosome-lysosome fusion (by stabilizing the SNARE component VAMP8 against CHIP-mediated ubiquitination and enhancing STX17-SNAP29-VAMP8 complex assembly), directing amino acid transporters (SLC1A5, LAT1) and SCAMP3 to lysosomes to support mTORC1 activation via lysosomal amino acid efflux, interacting with BAX to regulate apoptosis through the lysosome-cathepsin B pathway, and connecting innate immune TLR-MYD88-NF-κB signaling to selective autophagy (xenophagy) against intracellular pathogens via STING and p62."},"narrative":{"mechanistic_narrative":"DRAM1 is a multi-pass lysosomal transmembrane protein and a direct transcriptional target of p53 that couples stress sensing to autophagy and regulated cell death [PMID:16839881, PMID:17397945]. Its core lysosomal function is to drive autophagic flux: DRAM1 enhances lysosomal acidification by promoting V-ATPase activity and assembly, activates lysosomal proteases including cathepsin D, and accelerates autophagosome clearance [PMID:23696801, PMID:32943616]. At the membrane-fusion step, DRAM1 binds VAMP8 on lysosomes and competitively blocks CHIP/STUB1-mediated ubiquitination of VAMP8 at Lys68/72/75, stabilizing VAMP8 and promoting assembly of the STX17-SNAP29-VAMP8 SNARE complex to license autophagosome-lysosome fusion [PMID:40595569, PMID:40884094]. Beyond bulk autophagy, DRAM1 acts as a lysosomal scaffold that binds amino acid transporters SLC1A5 and LAT1 together with the carrier SCAMP3, directing them to lysosomes to support amino acid efflux and mTORC1 activation in an autophagy-independent manner with consequences for insulin signaling and adipocyte differentiation [PMID:31492633]. DRAM1 also governs cell death decisions: it interacts directly with BAX, protects it from autophagic degradation, and recruits it to lysosomes to trigger cathepsin B release, BID cleavage, and mitochondrial apoptosis [PMID:25633293]. In innate immunity, DRAM1 is induced downstream of TLR/IL1R-MYD88-NF-κB signaling and drives selective autophagy (xenophagy), LC3-associated phagocytosis, and acidification of pathogen-containing vesicles against intracellular bacteria, requiring STING and p62 [PMID:24922577, PMID:34731006, PMID:40950712]. Additional lysosome-organelle activities include EPS15-dependent EGFR endocytic degradation [PMID:32943616] and STIM1-mediated ER-lysosome tethering that regulates calcium homeostasis and ER-phagy, with lysosomal targeting dependent on the intact cytosol-facing C-terminal domain [PMID:39292746].","teleology":[{"year":2006,"claim":"Established DRAM1 as the molecular link between p53 and autophagy, answering how the tumor suppressor engages the lysosomal degradation system to execute cell death.","evidence":"RNAi knockdown, overexpression, lysosomal fractionation and p53-epistasis assays in mammalian cells","pmids":["16839881"],"confidence":"High","gaps":["Did not define the molecular activity of the lysosomal protein","Mechanism connecting DRAM1 induction to apoptosis unresolved"]},{"year":2007,"claim":"Defined the transcriptional control architecture, showing direct p53 binding at an upstream response element and a six-transmembrane topology, while extending regulation to the p53 family member p73.","evidence":"ChIP, luciferase reporter, isogenic p53 cell lines, GFP-fusion confocal microscopy; p73 isoform overexpression","pmids":["17397945","17304243"],"confidence":"High","gaps":["p73-induced autophagy is DRAM-independent, leaving DRAM's role in p73 signaling unclear","No structural validation of the six-TM model"]},{"year":2009,"claim":"Distinguished DRAM1 from its paralogue DRAM2 and showed upstream JNK signaling feeds DRAM induction, refining the regulatory inputs and establishing functional specificity within the family.","evidence":"Paralogue localization/function comparison; siRNA of DRAM and JNK with autophagy/apoptosis readouts","pmids":["19556885","19706754"],"confidence":"Medium","gaps":["Why DRAM2 localizes to lysosomes yet does not modulate autophagy unexplained","Direct biochemical activity still undefined"]},{"year":2012,"claim":"Resolved the lysosomal mechanism by which DRAM1 promotes flux—enhancing V-ATPase-driven acidification, cathepsin D activation, and autophagosome clearance—and linked DRAM1 to p62 trafficking and cancer cell invasion.","evidence":"siRNA knockdown, RFP-LC3 flux, lysosomal pH and cathepsin assays; p62 localization and invasion assays in glioblastoma stem cells","pmids":["23696801","22525272","22082963"],"confidence":"High","gaps":["How DRAM1 mechanistically promotes V-ATPase activity not yet shown","Splice-variant-specific functions only partially mapped"]},{"year":2013,"claim":"Identified DRAM1 as a direct BAX partner and a node in viral-stress-induced death, establishing a transcription-independent apoptotic mechanism via lysosomal recruitment of BAX and cathepsin B release.","evidence":"Co-IP, BAX half-life and cathepsin B/cytochrome c assays; HIV infection model with p53/DRAM knockdown","pmids":["25633293","23658518"],"confidence":"High","gaps":["Structural basis of DRAM1-BAX interaction unknown","How lysosomal BAX recruitment is gated relative to autophagy not defined"]},{"year":2014,"claim":"Connected DRAM1 to innate immune defense, showing a p53-independent MYD88-NF-κB axis induces DRAM1 to drive xenophagy against mycobacteria, and revealed AKT-dependent control of DRAM mitochondrial translocation.","evidence":"MYD88/NF-κB/STING/p62 epistasis in zebrafish and human macrophages; p-AKT/DRAM co-IP and localization in HCC cells","pmids":["24922577","24556693"],"confidence":"High","gaps":["Molecular basis of STING/p62 requirement for DRAM1 xenophagy not defined","How p-AKT binding sequesters DRAM in cytoplasm structurally unclear"]},{"year":2018,"claim":"Expanded DRAM1's autophagy machinery contacts, showing it binds Atg7 to promote Atg12-Atg5 conjugation and is required for alternative Atg5-independent autophagy and isolation-membrane closure downstream of p53.","evidence":"Co-IP with Atg7/Atg5/Atg12, mRFP-GFP-LC3 flux, EM of isolation membranes, Atg5/p53 epistasis","pmids":["30144448","31225467"],"confidence":"Medium","gaps":["Reconciliation of Atg7-dependent and Atg5-independent roles unresolved","Direct biochemical effect of DRAM1 on conjugation machinery not reconstituted"]},{"year":2019,"claim":"Revealed an autophagy-independent metabolic function: DRAM1 scaffolds amino acid transporters and SCAMP3 at lysosomes to drive amino acid efflux and mTORC1 activation, with whole-body consequences for glycemic and adipocyte biology, while also influencing Golgi/secretory trafficking and IGF-1R signaling.","evidence":"Co-IP, lysosomal fractionation, amino acid efflux and mTORC1 assays, DRAM1 knockout mouse; VSVG and CI-MPR trafficking assays","pmids":["31492633","30902093","31356858"],"confidence":"High","gaps":["Mechanism by which DRAM1 selects transporter cargo for lysosomal delivery unknown","Apparent opposing effects on mTORC1/PI3K-Akt across contexts not reconciled"]},{"year":2020,"claim":"Defined DRAM1 as a recruiter of V-ATPase and EPS15 to drive EGFR endocytic degradation and confirmed in vivo that vesicle acidification underlies pathogen clearance, with loss leading to premature pyroptosis.","evidence":"BioID proteomics, EPS15 co-IP, lysosomal pH and EGFR degradation, xenografts; zebrafish dram1 CRISPR with caspa/gsdmeb epistasis","pmids":["32943616","32332700"],"confidence":"High","gaps":["How DRAM1 physically enhances V-ATPase assembly remains mechanistically open","Link between failed acidification and pyroptosis induction not defined"]},{"year":2021,"claim":"Showed DRAM1 binds STOM and PKM2 to control lysosomal membrane permeabilization and extracellular vesicle/ectosome secretion from hepatocytes, extending its role to lipid- and ethanol-driven liver pathology and immune crosstalk.","evidence":"Co-IP, DRAM knockout and liver-specific overexpression mice, LMP and EV/ectosome assays, macrophage activation","pmids":["34731006","35036051"],"confidence":"Medium","gaps":["Whether STOM and PKM2 interactions are direct or scaffold-mediated unclear","Mechanism coupling LMP to vesicle secretion not resolved"]},{"year":2024,"claim":"Established DRAM1 as an ER-lysosome contact factor: it tethers lysosomes to the ER via STIM1, controlling calcium homeostasis, ER stress, and ER-phagy, and mapped lysosomal targeting to its cytosol-facing C-terminal domain.","evidence":"Co-IP, calcium imaging, ER morphology and ER-phagy assays, AMPK-ULK1 readouts, domain-deletion mutants, STIM1 rescue","pmids":["39292746"],"confidence":"High","gaps":["Physiological versus overexpression-driven STIM1 effects need separation","Structural determinants of the DRAM1-STIM1 contact undefined"]},{"year":2025,"claim":"Defined the molecular mechanism of DRAM1 at the fusion step—competitive inhibition of CHIP/STUB1 ubiquitination of VAMP8 to stabilize it and promote STX17-SNAP29-VAMP8 SNARE assembly—and tied this to HCC metastasis, while also implicating DRAM1 in AMPK-driven pro-senescent autophagy.","evidence":"Co-IP, VAMP8 lysine mutagenesis, ubiquitination and SNARE assembly assays, ATG5/ATG7 KO, mouse and zebrafish metastasis models; 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omega","url":"https://pubmed.ncbi.nlm.nih.gov/42040442","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.18.24319252","title":"Bayesian Inference of Nosocomial<i>Methicillin-resistant Staphylococcus aureus</i>Transmission Rates in an Urban Safety-Net Hospital","date":"2024-12-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.18.24319252","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48942,"output_tokens":7948,"usd":0.133023,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17125,"output_tokens":4873,"usd":0.103725,"stage2_stop_reason":"end_turn"},"total_usd":0.236748,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"DRAM1 (DRAM) is a direct transcriptional target of p53 that encodes a lysosomal protein; p53 induces autophagy in a DRAM-dependent manner, and DRAM is essential for p53-mediated apoptosis.\",\n      \"method\": \"RNAi knockdown, overexpression, lysosomal localization by cell fractionation/imaging, p53-dependent induction assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA knockdown, overexpression, subcellular fractionation, genetic epistasis with p53), replicated across subsequent independent studies\",\n      \"pmids\": [\"16839881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TA-p73 transcriptionally regulates DRAM but, unlike p53, p73's induction of autophagy is DRAM-independent; deltaN-p73 negatively regulates p53-induced and p73-induced autophagy but not starvation-induced autophagy.\",\n      \"method\": \"RNAi knockdown of DRAM, overexpression of p73 isoforms, autophagy flux assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal RNAi and OE in one lab, two orthogonal methods, single lab\",\n      \"pmids\": [\"17304243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FLJ11259/DRAM1 is a direct p53 target gene with a functional p53 response element 22.3 kb upstream of the first coding exon; p53 binds this element in vivo (ChIP), and binding is enhanced after cisplatin treatment. The protein contains six transmembrane domains and localizes in a punctate cytoplasmic pattern.\",\n      \"method\": \"p53 siRNA knockdown, isogenic p53+/+ vs p53-suppressed cell lines, luciferase reporter assay, chromatin immunoprecipitation, GFP-fusion confocal microscopy\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP confirming direct p53 binding, reporter assay, siRNA validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17397945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DRAM1 is a lysosomal protein; a closely related paralogue DRAM2 (45% identity) also localizes to lysosomes but does not modulate autophagy on overexpression and is not induced by p53 or p73. Drosophila DmDRAM, the single fly orthologue, retains the ability to modulate autophagy.\",\n      \"method\": \"Overexpression with subcellular localization (immunofluorescence), autophagy flux assays, comparison of p53/p73 induction across paralogues\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — localization and functional assays with overexpression, single lab, two orthogonal readouts\",\n      \"pmids\": [\"19556885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JNK activation is required upstream of DRAM induction by 2-methoxyestradiol; JNK promotes DRAM expression in a p53-partially-regulated manner, and DRAM silencing reduces both autophagy and apoptosis triggered by 2-ME.\",\n      \"method\": \"siRNA knockdown of DRAM and JNK, pharmacological JNK inhibition, autophagy/apoptosis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with dual functional readouts (autophagy and apoptosis), single lab\",\n      \"pmids\": [\"19706754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DRAM1 promotes autophagy flux by enhancing lysosomal acidification (V-ATPase activity), promoting autophagosome-lysosome fusion, and activating lysosomal cathepsin D; siRNA knockdown of DRAM1 reduces lysosomal V-ATPase activity and slows clearance of autophagosomes.\",\n      \"method\": \"siRNA knockdown, RFP-LC3 flux assay, lysosomal pH measurement, cathepsin D activity assay, rapamycin washout experiment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (flux, pH, cathepsin activity, autophagosome clearance) in one study, single lab\",\n      \"pmids\": [\"23696801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DRAM1 regulates p62 localization to autophagosomes and its autophagy-mediated degradation; DRAM1 knockdown decreases this process. DRAM1 and p62 cooperatively regulate cell motility and invasion in glioblastoma stem cells, associated with reduced ATP and lactate levels. Starvation- or mTOR/PI3K inhibition-induced autophagy is not affected by DRAM1 or p62 knockdown.\",\n      \"method\": \"siRNA knockdown, immunofluorescence localization of p62, invasion/migration assays, metabolic measurements\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA knockdown with functional (invasion) and biochemical (p62 localization, metabolism) readouts, single lab\",\n      \"pmids\": [\"22525272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DRAM-1 encodes multiple p53-inducible splice variants (SV1, SV4, SV5); SV1 localizes to lysosomes/endosomes, SV4 partially localizes to peroxisomes and ER, SV5 partially localizes to autophagosomes and ER. SV4 and SV5 modulate autophagy without inducing programmed cell death.\",\n      \"method\": \"Cloning of splice variants, immunofluorescence co-localization with organelle markers, autophagy assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct subcellular localization experiments with multiple organelle markers, autophagy functional assay, single lab\",\n      \"pmids\": [\"22082963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DRAM1 interacts directly with BAX protein, inhibiting BAX degradation by autophagy, thereby increasing BAX protein levels in a transcription-independent manner. DRAM1 recruits BAX to lysosomes, triggering lysosomal cathepsin B release and BID cleavage, leading to mitochondrial cytochrome c release and caspase-3 activation.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown, BAX half-life measurement, cathepsin B/cytochrome c release assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — co-IP demonstrating direct DRAM1-BAX interaction, multiple downstream functional assays, half-life measurement, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25633293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HIV infection induces DRAM expression in a p53-dependent manner in CD4+ T cells; DRAM knockdown inhibits autophagy and lysosomal membrane permeabilization (LMP), cytochrome C release, MOMP, and cell death, but increases viral production.\",\n      \"method\": \"siRNA knockdown of DRAM and p53, LMP assay, cytochrome C release, MOMP measurement, viral titer\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple functional readouts (LMP, MOMP, viral replication), single lab\",\n      \"pmids\": [\"23658518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DRAM1 expression is induced downstream of the TLR/IL1R-MYD88-NF-κB innate immune sensing pathway in response to mycobacterial infection; DRAM1 activates selective autophagy against mycobacteria in a p53-independent manner requiring STING and p62/SQSTM1.\",\n      \"method\": \"MYD88/NF-κB inhibition, siRNA knockdown of DRAM1, overexpression, co-localization with Mtb, zebrafish and human macrophage infection models\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (MYD88, NF-κB, STING, p62 knockdowns), reciprocal gain- and loss-of-function, replicated in two model systems (zebrafish and human macrophages)\",\n      \"pmids\": [\"24922577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Phosphorylated AKT (p-AKT) binds DRAM in the cytoplasm, blocking DRAM translocation to mitochondria; inactivation of PI3K/AKT pathway rescues DRAM translocation to mitochondria, where DRAM induces mitophagy and apoptosis in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation of p-AKT and DRAM, immunofluorescence tracking of DRAM localization, PI3K inhibition, siRNA knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating p-AKT/DRAM interaction, localization assay with functional consequence, single lab\",\n      \"pmids\": [\"24556693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DRAM-3 (TMEM150B), a DRAM1-related protein, localizes to lysosomes/autolysosomes, endosomes, and plasma membrane; it modulates autophagy flux and promotes cell survival under glucose deprivation in an autophagy-independent manner.\",\n      \"method\": \"Immunofluorescence localization, CRISPR/Cas9 disruption, autophagy flux assays, clonogenic survival assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knockout confirming endogenous role, localization, flux assays, single lab\",\n      \"pmids\": [\"25929859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Dram1 is required for genotoxic stress-induced alternative (Atg5-independent) autophagy; Dram1 functions in the closure of isolation membranes downstream of p53 in this alternative autophagy pathway.\",\n      \"method\": \"Dram1 overexpression/knockdown in cells with or without Atg5, electron microscopy of isolation membranes, epistasis with p53\",\n      \"journal\": \"Cell stress\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with Atg5 and p53, morphological EM analysis, single lab\",\n      \"pmids\": [\"31225467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DRAM1 interacts with Atg7 (but not directly with Atg5 or Atg12), promoting formation of the Atg12-Atg5 conjugate; DRAM1 overexpression restores autophagic flux and autophagosome-to-autophagolysosome conversion in ischemic cardiomyocytes. Atg7 siRNA abolishes these effects.\",\n      \"method\": \"Co-immunoprecipitation (DRAM1 with Atg7, Atg5, Atg12), mRFP-GFP-LC3 flux assay, siRNA knockdown, adenoviral overexpression in rat AMI model\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with negative controls (no Atg5/Atg12 interaction), flux assay, genetic rescue, single lab\",\n      \"pmids\": [\"30144448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DRAM1 binds the membrane carrier protein SCAMP3 and amino acid transporters SLC1A5 and LAT1, directing them to lysosomes to permit efficient efflux of amino acids from lysosomes into the cytoplasm, which is required for mTORC1 activation. Loss of DRAM1 impairs mTORC1 activation, insulin signaling, glycemic balance, and adipocyte differentiation. This effect is autophagy-independent.\",\n      \"method\": \"Co-immunoprecipitation, lysosomal fractionation, amino acid efflux assays, DRAM-1 knockout mouse, mTORC1 activity measurements, adipocyte differentiation assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple binding partners identified by co-IP, lysosomal fractionation, in vivo knockout mouse, multiple functional readouts across cell types and tissues, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31492633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DRAM1 inhibits rpS6 phosphorylation in an mTORC1-dependent manner and inhibits activation of the PI3K-Akt pathway stimulated by growth factors; DRAM1 localizes at the plasma membrane and regulates phosphorylation of the IGF-1 receptor.\",\n      \"method\": \"FLAG-DRAM1 overexpression, siRNA knockdown, Western blot for phospho-rpS6/Akt/IGF-1R, immunostaining for DRAM1 localization, CCK-8 and colony formation assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — overexpression and knockdown with pathway activity readouts, localization data, single lab\",\n      \"pmids\": [\"30902093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DRAM1 deficiency causes fragmentation of the Golgi apparatus; DRAM1 is partially localized in the Golgi, and its knockdown delays ER-to-plasma membrane transport of VSVG-GFP and impedes retrograde trafficking of CI-MPR from plasma membrane to Golgi.\",\n      \"method\": \"siRNA knockdown, immunofluorescence with Golgi markers, ts045-VSVG-GFP transport assay, CI-MPR trafficking assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — knockdown with functional vesicular transport readouts and localization data, single lab\",\n      \"pmids\": [\"31356858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dram1 deficiency in zebrafish reduces phagosome/vesicle acidification of Mycobacterium marinum-containing vesicles, impairs autophagic targeting of Mm, and leads to premature pyroptotic death of infected macrophages via caspase a/gasdermin Eb; knockdown of caspa and gsdmeb reverts the increased bacterial burden.\",\n      \"method\": \"Zebrafish dram1 CRISPR mutant, in vivo imaging of autophagic targeting, LysoTracker acidification assay, caspa/gsdmeb knockdown epistasis, RNA-seq\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR knockout, in vivo imaging, genetic epistasis with pyroptosis effectors, multiple readouts in vivo\",\n      \"pmids\": [\"32332700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DRAM1 interacts with EPS15 to promote EGFR endocytosis, and recruits V-ATPase (V-ATP6V1 subunit) to lysosomes, increasing lysosomal V-ATPase assembly, lowering lysosomal pH, and activating lysosomal proteases, resulting in accelerated EGFR lysosomal degradation and suppression of EGFR signaling.\",\n      \"method\": \"Proximity labeling (BioID) followed by proteomics, co-IP of DRAM1 with EPS15, lysosomal pH measurement, EGFR degradation assay, xenograft tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — proximity labeling proteomics plus co-IP validation, lysosomal pH measurement, EGFR trafficking assay, in vivo xenograft, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32943616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DRAM interacts with stomatin (STOM) and promotes its lysosomal localization; fatty acid-induced DRAM enhances lysosomal membrane permeabilization (LMP) and promotes exosome secretion from hepatocytes. DRAM knockout reverses high-fat diet-induced increase in exosome secretion.\",\n      \"method\": \"Co-immunoprecipitation of DRAM and STOM, DRAM knockout mouse model, siRNA knockdown, LMP assay, exosome quantification\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, DRAM KO mouse, siRNA with functional exosome readout, single lab\",\n      \"pmids\": [\"34731006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DRAM1 interacts with PKM2 and increases PKM2 levels at the plasma membrane; ethanol-induced DRAM1 in hepatocytes increases secretion of PKM2-enriched extracellular vesicles/ectosomes that promote macrophage M1 activation.\",\n      \"method\": \"Co-immunoprecipitation of DRAM1 and PKM2, DRAM1 knockout and liver-specific overexpression mouse models, ectosome isolation, macrophage activation assay\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in vivo KO and OE mouse models, functional macrophage activation readout, single lab\",\n      \"pmids\": [\"35036051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DRAM1 interacts with STIM1 to tether lysosomes to the ER, perturbing STIM1 function in maintaining intracellular calcium homeostasis; excess DRAM1 disrupts ER structure, triggers ER stress, and induces protective ER-phagy. Lysosomal localization of DRAM1 requires its intact cytosol-facing C-terminal domain. STIM1 overexpression restores calcium homeostasis, ER stress response, and AMPK-ULK1 signaling in cells with excess DRAM1.\",\n      \"method\": \"Co-immunoprecipitation of DRAM1 and STIM1, calcium imaging, ER morphology analysis, ER-phagy assay, AMPK-ULK1 signaling readouts, domain-deletion mutants for localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — co-IP, domain mutagenesis for localization, calcium homeostasis assay, ER-phagy, genetic rescue with STIM1 OE, multiple orthogonal methods in one study\",\n      \"pmids\": [\"39292746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In macrophages, DRAM1 localizes to mycobacteria-containing vesicles post-phagocytosis; DRAM1 knockdown reduces LC3 recruitment to mycobacteria and acidification of mycobacteria-containing vesicles, and reduces fusion with LAMP1-positive lysosomes, impairing intracellular killing.\",\n      \"method\": \"DRAM1 siRNA knockdown in RAW264.7 macrophages, immunofluorescence co-localization with LC3/LysoTracker/LAMP1, bacterial survival assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA with multiple localization and functional readouts, single lab\",\n      \"pmids\": [\"36980169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DRAM1 and xenophagy receptors Optn and p62 independently promote host defense against Mycobacterium marinum; Dram1 overexpression can compensate for loss of Optn or p62, and vice versa. Dram1 overexpression restores Lc3-Mm interaction in optn/p62 double mutants, indicating Dram1-mediated defense does not rely on specific xenophagy receptors.\",\n      \"method\": \"Single and double knockout zebrafish lines, overexpression rescue experiments, Lc3-Mm co-localization imaging, bacterial burden quantification\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis using KO/OE in zebrafish, co-localization readout, single lab\",\n      \"pmids\": [\"38264729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DRAM1 directly binds VAMP8 on lysosomes; this interaction is enhanced upon autophagy induction. DRAM1 competitively inhibits CHIP/STUB1-mediated ubiquitination of VAMP8 at Lys68, Lys72, and Lys75, stabilizing lysosomal VAMP8 and promoting assembly of the STX17-SNAP29-VAMP8 SNARE complex, thereby facilitating autophagosome-lysosome fusion and autophagic flux. DRAM1-mediated VAMP8 stabilization promotes HCC cell extravasation.\",\n      \"method\": \"Co-immunoprecipitation of DRAM1-VAMP8 and STUB1-VAMP8, ubiquitination assay, site-directed mutagenesis of VAMP8 lysines, SNARE complex assembly assay, ATG5/ATG7 knockout, mouse and zebrafish metastasis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-IP, site-directed mutagenesis identifying ubiquitination sites, SNARE assembly assay, genetic rescue with ATG5/ATG7 KO, replicated in mouse and zebrafish in vivo models\",\n      \"pmids\": [\"40595569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DRAM1 activates AMPK and mediates pro-senescent autophagy (DMPA) in response to aging-associated metabolic cues (N-acetylhistamine, phosphatidylethanolamine); DRAM1-mediated autophagy in this context does not notably degrade SQSTM1/p62, distinguishing it from general macroautophagy.\",\n      \"method\": \"DRAM1 overexpression/knockdown in human MSCs and mouse hepatocytes, metabolomics, AMPK activity assay, autophagy flux assay, senescence markers, N-AcHA and ethanolamine supplementation\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — DRAM1 manipulation with AMPK activity and senescence readouts, metabolomics correlation, single lab\",\n      \"pmids\": [\"41037659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Dram1/DRAM1 promotes LC3-associated phagocytosis (LAP) of Salmonella Typhimurium; Dram1 knockdown or mutation reduces GFP-Lc3 association with Salmonella and abolishes phagosomal NADPH oxidase-dependent ROS response to the bacteria. These results were confirmed in zebrafish and murine RAW264.7 macrophages.\",\n      \"method\": \"Morpholino knockdown, CRISPR mutation, mRNA overexpression in zebrafish, Salmonella ROS biosensor, GFP-Lc3 imaging, siRNA in RAW264.7 macrophages\",\n      \"journal\": \"Autophagy reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in two model systems with ROS biosensor and LC3 imaging readouts, single lab\",\n      \"pmids\": [\"40950712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p73-regulated DRAM-1 is functionally required for neutrophil differentiation of APL cells; DRAM-1 expression is induced during ATRA-induced differentiation of NB4 APL cells, and its knockdown impairs this differentiation. p73 inhibition prevents both differentiation and DRAM-1 induction.\",\n      \"method\": \"siRNA knockdown of DRAM-1, ATRA differentiation assay, p73 inhibition, DRAM-1 expression measurement by qPCR/Western blot\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — siRNA knockdown with differentiation phenotype and p73 epistasis, single lab\",\n      \"pmids\": [\"22981223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Serum deprivation induces DRAM expression in liver cancer cells through epigenetic remodeling: active chromatin marks (diacetyl-H3, tetra-acetyl-H4, trimethyl-H3K4) increase and repressive mark (dimethyl-H3K9) decreases at the DRAM core promoter. The chromatin remodeling factor Brg-1 is enriched at the DRAM promoter and is required for serum deprivation-induced DRAM expression.\",\n      \"method\": \"ChIP for histone marks and Brg-1 at DRAM promoter, Brg-1 knockdown, luciferase reporter for DRAM promoter activity\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with multiple histone marks plus functional Brg-1 knockdown, single lab\",\n      \"pmids\": [\"23251372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DRAM1 interacts with VAMP8; this interaction is enhanced by autophagy stimulation. DRAM1 preferentially promotes autophagosome-lysosome fusion by enhancing assembly of the STX17-SNAP29-VAMP8 SNARE complex, and inhibits VAMP8 ubiquitination at Lys68, Lys72, and Lys75 by competing with CHIP/STUB1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, mutagenesis of VAMP8 lysine residues, SNARE complex co-IP, autophagy flux assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — co-IP, site-directed mutagenesis, SNARE complex assembly assay, ubiquitination assay, corroborates PMID:40595569 from same group\",\n      \"pmids\": [\"40884094\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DRAM1 is a multi-pass lysosomal transmembrane protein and direct transcriptional target of p53 that regulates autophagy flux by promoting lysosomal acidification (via V-ATPase assembly), facilitating autophagosome-lysosome fusion (by stabilizing the SNARE component VAMP8 against CHIP-mediated ubiquitination and enhancing STX17-SNAP29-VAMP8 complex assembly), directing amino acid transporters (SLC1A5, LAT1) and SCAMP3 to lysosomes to support mTORC1 activation via lysosomal amino acid efflux, interacting with BAX to regulate apoptosis through the lysosome-cathepsin B pathway, and connecting innate immune TLR-MYD88-NF-κB signaling to selective autophagy (xenophagy) against intracellular pathogens via STING and p62.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DRAM1 is a multi-pass lysosomal transmembrane protein and a direct transcriptional target of p53 that couples stress sensing to autophagy and regulated cell death [#0, #2]. Its core lysosomal function is to drive autophagic flux: DRAM1 enhances lysosomal acidification by promoting V-ATPase activity and assembly, activates lysosomal proteases including cathepsin D, and accelerates autophagosome clearance [#5, #19]. At the membrane-fusion step, DRAM1 binds VAMP8 on lysosomes and competitively blocks CHIP/STUB1-mediated ubiquitination of VAMP8 at Lys68/72/75, stabilizing VAMP8 and promoting assembly of the STX17-SNAP29-VAMP8 SNARE complex to license autophagosome-lysosome fusion [#25, #30]. Beyond bulk autophagy, DRAM1 acts as a lysosomal scaffold that binds amino acid transporters SLC1A5 and LAT1 together with the carrier SCAMP3, directing them to lysosomes to support amino acid efflux and mTORC1 activation in an autophagy-independent manner with consequences for insulin signaling and adipocyte differentiation [#15]. DRAM1 also governs cell death decisions: it interacts directly with BAX, protects it from autophagic degradation, and recruits it to lysosomes to trigger cathepsin B release, BID cleavage, and mitochondrial apoptosis [#8]. In innate immunity, DRAM1 is induced downstream of TLR/IL1R-MYD88-NF-\\u03baB signaling and drives selective autophagy (xenophagy), LC3-associated phagocytosis, and acidification of pathogen-containing vesicles against intracellular bacteria, requiring STING and p62 [#10, #20, #27]. Additional lysosome-organelle activities include EPS15-dependent EGFR endocytic degradation [#19] and STIM1-mediated ER-lysosome tethering that regulates calcium homeostasis and ER-phagy, with lysosomal targeting dependent on the intact cytosol-facing C-terminal domain [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established DRAM1 as the molecular link between p53 and autophagy, answering how the tumor suppressor engages the lysosomal degradation system to execute cell death.\",\n      \"evidence\": \"RNAi knockdown, overexpression, lysosomal fractionation and p53-epistasis assays in mammalian cells\",\n      \"pmids\": [\"16839881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular activity of the lysosomal protein\", \"Mechanism connecting DRAM1 induction to apoptosis unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the transcriptional control architecture, showing direct p53 binding at an upstream response element and a six-transmembrane topology, while extending regulation to the p53 family member p73.\",\n      \"evidence\": \"ChIP, luciferase reporter, isogenic p53 cell lines, GFP-fusion confocal microscopy; p73 isoform overexpression\",\n      \"pmids\": [\"17397945\", \"17304243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"p73-induced autophagy is DRAM-independent, leaving DRAM's role in p73 signaling unclear\", \"No structural validation of the six-TM model\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Distinguished DRAM1 from its paralogue DRAM2 and showed upstream JNK signaling feeds DRAM induction, refining the regulatory inputs and establishing functional specificity within the family.\",\n      \"evidence\": \"Paralogue localization/function comparison; siRNA of DRAM and JNK with autophagy/apoptosis readouts\",\n      \"pmids\": [\"19556885\", \"19706754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why DRAM2 localizes to lysosomes yet does not modulate autophagy unexplained\", \"Direct biochemical activity still undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the lysosomal mechanism by which DRAM1 promotes flux—enhancing V-ATPase-driven acidification, cathepsin D activation, and autophagosome clearance—and linked DRAM1 to p62 trafficking and cancer cell invasion.\",\n      \"evidence\": \"siRNA knockdown, RFP-LC3 flux, lysosomal pH and cathepsin assays; p62 localization and invasion assays in glioblastoma stem cells\",\n      \"pmids\": [\"23696801\", \"22525272\", \"22082963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DRAM1 mechanistically promotes V-ATPase activity not yet shown\", \"Splice-variant-specific functions only partially mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified DRAM1 as a direct BAX partner and a node in viral-stress-induced death, establishing a transcription-independent apoptotic mechanism via lysosomal recruitment of BAX and cathepsin B release.\",\n      \"evidence\": \"Co-IP, BAX half-life and cathepsin B/cytochrome c assays; HIV infection model with p53/DRAM knockdown\",\n      \"pmids\": [\"25633293\", \"23658518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of DRAM1-BAX interaction unknown\", \"How lysosomal BAX recruitment is gated relative to autophagy not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected DRAM1 to innate immune defense, showing a p53-independent MYD88-NF-\\u03baB axis induces DRAM1 to drive xenophagy against mycobacteria, and revealed AKT-dependent control of DRAM mitochondrial translocation.\",\n      \"evidence\": \"MYD88/NF-\\u03baB/STING/p62 epistasis in zebrafish and human macrophages; p-AKT/DRAM co-IP and localization in HCC cells\",\n      \"pmids\": [\"24922577\", \"24556693\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of STING/p62 requirement for DRAM1 xenophagy not defined\", \"How p-AKT binding sequesters DRAM in cytoplasm structurally unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded DRAM1's autophagy machinery contacts, showing it binds Atg7 to promote Atg12-Atg5 conjugation and is required for alternative Atg5-independent autophagy and isolation-membrane closure downstream of p53.\",\n      \"evidence\": \"Co-IP with Atg7/Atg5/Atg12, mRFP-GFP-LC3 flux, EM of isolation membranes, Atg5/p53 epistasis\",\n      \"pmids\": [\"30144448\", \"31225467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of Atg7-dependent and Atg5-independent roles unresolved\", \"Direct biochemical effect of DRAM1 on conjugation machinery not reconstituted\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed an autophagy-independent metabolic function: DRAM1 scaffolds amino acid transporters and SCAMP3 at lysosomes to drive amino acid efflux and mTORC1 activation, with whole-body consequences for glycemic and adipocyte biology, while also influencing Golgi/secretory trafficking and IGF-1R signaling.\",\n      \"evidence\": \"Co-IP, lysosomal fractionation, amino acid efflux and mTORC1 assays, DRAM1 knockout mouse; VSVG and CI-MPR trafficking assays\",\n      \"pmids\": [\"31492633\", \"30902093\", \"31356858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which DRAM1 selects transporter cargo for lysosomal delivery unknown\", \"Apparent opposing effects on mTORC1/PI3K-Akt across contexts not reconciled\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined DRAM1 as a recruiter of V-ATPase and EPS15 to drive EGFR endocytic degradation and confirmed in vivo that vesicle acidification underlies pathogen clearance, with loss leading to premature pyroptosis.\",\n      \"evidence\": \"BioID proteomics, EPS15 co-IP, lysosomal pH and EGFR degradation, xenografts; zebrafish dram1 CRISPR with caspa/gsdmeb epistasis\",\n      \"pmids\": [\"32943616\", \"32332700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DRAM1 physically enhances V-ATPase assembly remains mechanistically open\", \"Link between failed acidification and pyroptosis induction not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed DRAM1 binds STOM and PKM2 to control lysosomal membrane permeabilization and extracellular vesicle/ectosome secretion from hepatocytes, extending its role to lipid- and ethanol-driven liver pathology and immune crosstalk.\",\n      \"evidence\": \"Co-IP, DRAM knockout and liver-specific overexpression mice, LMP and EV/ectosome assays, macrophage activation\",\n      \"pmids\": [\"34731006\", \"35036051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STOM and PKM2 interactions are direct or scaffold-mediated unclear\", \"Mechanism coupling LMP to vesicle secretion not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established DRAM1 as an ER-lysosome contact factor: it tethers lysosomes to the ER via STIM1, controlling calcium homeostasis, ER stress, and ER-phagy, and mapped lysosomal targeting to its cytosol-facing C-terminal domain.\",\n      \"evidence\": \"Co-IP, calcium imaging, ER morphology and ER-phagy assays, AMPK-ULK1 readouts, domain-deletion mutants, STIM1 rescue\",\n      \"pmids\": [\"39292746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological versus overexpression-driven STIM1 effects need separation\", \"Structural determinants of the DRAM1-STIM1 contact undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the molecular mechanism of DRAM1 at the fusion step—competitive inhibition of CHIP/STUB1 ubiquitination of VAMP8 to stabilize it and promote STX17-SNAP29-VAMP8 SNARE assembly—and tied this to HCC metastasis, while also implicating DRAM1 in AMPK-driven pro-senescent autophagy.\",\n      \"evidence\": \"Co-IP, VAMP8 lysine mutagenesis, ubiquitination and SNARE assembly assays, ATG5/ATG7 KO, mouse and zebrafish metastasis models; MSC/hepatocyte AMPK and senescence assays\",\n      \"pmids\": [\"40595569\", \"40884094\", \"41037659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DRAM1 competes with CHIP at VAMP8 structurally unresolved\", \"Relationship between SNARE stabilization and the distinct p62-sparing senescent autophagy unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity intrinsic to the DRAM1 transmembrane protein—how it mechanistically promotes V-ATPase assembly and selects diverse cargo (transporters, BAX, VAMP8, STIM1) at the lysosomal membrane—remains undefined, as does a structural model unifying its many context-dependent partnerships.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of DRAM1 or its complexes\", \"No reconstituted assay defining a primary molecular activity\", \"Determinants of cargo/partner selectivity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [15, 19, 25, 30, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 25, 30, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 2, 3, 5, 15, 19, 22]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [16, 12]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [22, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 5, 25, 30, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 9, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 20, 23, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 16, 19, 22]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [19, 17, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BAX\", \"VAMP8\", \"SLC1A5\", \"LAT1\", \"SCAMP3\", \"EPS15\", \"STIM1\", \"STOM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}