{"gene":"ATL3","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2019,"finding":"ATL3 functions as a receptor for tubular ER-phagy by specifically binding to GABARAP (but not LC3) subfamily proteins via two GABARAP interaction motifs (GIMs). This interaction is essential for ATL3-mediated selective autophagy of tubular ER upon starvation.","method":"Co-immunoprecipitation, binding assays, starvation-induced autophagy assays, fluorescence microscopy","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying specific binding partners, functional validation with loss-of-function, independently corroborated by multiple subsequent studies","pmids":["30773365"],"is_preprint":false},{"year":2019,"finding":"HSAN I-associated ATL3 mutations Y192C and P338R disrupt ATL3's association with GABARAP and impair ATL3's function in ER-phagy, linking defective ER-phagy to the disease mechanism.","method":"Co-immunoprecipitation with mutant constructs, autophagy flux assays in cells expressing disease mutants","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutant-specific Co-IP and functional autophagy assay, replicated in disease patient context by independent studies","pmids":["30773365","30680846"],"is_preprint":false},{"year":2014,"finding":"ATL3 is a dynamin-like GTPase enriched at three-way junctions of the tubular ER network. The disease-causing mutation p.Tyr192Cys causes mutant ATL3 to fail to localize to branch points and instead disrupts the tubular ER structure, suggesting a dominant-negative effect on ER morphology.","method":"Immunofluorescence microscopy of wild-type and mutant ATL3 localization in cells, patient-derived samples","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence, replicated across multiple subsequent studies with the same mutation","pmids":["24459106"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of ATL3 reveals discrete temporal steps in the GTPase catalytic cycle, including nucleotide binding, hydrolysis, ATL dimerization, and phosphate release. The structure suggests a mechanism for displacement of the catalytic Mg2+ ion following GTP hydrolysis to reset the cycle.","method":"X-ray crystallography, biochemical GTPase assays comparing ATL1 and ATL3 isoforms","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biochemical functional validation, single lab but multiple orthogonal methods","pmids":["28602821"],"is_preprint":false},{"year":2016,"finding":"Triple knockout of all three atlastins (Atl1/2/3) in mammalian NIH-3T3 cells using CRISPR/Cas9 markedly disrupts ER morphology, specifically impairing formation of three-way ER tubule junctions. This phenotype can be rescued by any single human atlastin or distant orthologs (Sey1p, RHD3), establishing atlastins as necessary for polygonal ER network formation.","method":"CRISPR/Cas9 knockout, rescue experiments with heterologous orthologs, fluorescence microscopy of ER morphology","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype and rescue experiments with multiple orthologs, multiple orthogonal methods","pmids":["27669642"],"is_preprint":false},{"year":2019,"finding":"ATL3 mutation Y192C reduces the complexity of the tubular ER network, delays ER export by reducing the number of ER exit sites, reduces autophagy, fragments the Golgi, and causes nuclear malformation. In primary neurons, ATL3 Y192C does not localize to the growing axon, resulting in axon growth deficits.","method":"Expression of disease mutant in cultured cells and primary neurons, patient-derived fibroblasts, immunofluorescence, autophagosome quantification","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ER exit site counting, Golgi morphology, nuclear shape, axon growth) in both cell lines and patient-derived fibroblasts","pmids":["30666337"],"is_preprint":false},{"year":2019,"finding":"Disease-causing ATL3 mutations (Y192C and P338R) increase the number of ER-mitochondria contact sites in HeLa cells and patient-derived fibroblasts, reflected in higher phospholipid metabolism, upregulated autophagy, augmented Ca2+ crosstalk between ER and mitochondria, and decreased mitochondrial motility. Neurons expressing these mutations show strongly decreased numbers of axonal mitochondria.","method":"Electron microscopy of ER-mitochondria contacts, Ca2+ imaging, mitochondrial motility tracking, phospholipid analysis, patient-derived fibroblasts, neuronal culture","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EM, Ca2+ imaging, lipid analysis, live imaging) in both cell lines and patient cells","pmids":["30339187"],"is_preprint":false},{"year":2019,"finding":"ATL3 interacts with Zika virus nonstructural proteins NS2A and NS2B3, is recruited to viral replication sites, and is required for efficient ZIKV replication. Depletion of ATL proteins significantly decreased intracellular viral protein levels and released virus.","method":"Co-immunoprecipitation of ATL3 with viral NS2A/NS2B3, siRNA knockdown, immunofluorescence colocalization at replication sites, viral titer measurements","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and colocalization at replication sites with KD phenotype, single lab","pmids":["31534046"],"is_preprint":false},{"year":2017,"finding":"Atlastin3 (Atl3/Sey1p) localizes to early Legionella-containing vacuoles (LCVs) and is critical for LCV expansion and pathogen replication. GTP (but not GDP) catalyzes Sey1-dependent aggregation of purified ER-positive LCVs in vitro. A catalytically inactive dominant-negative GTPase mutant or ATL3 depletion restricts replication and impairs LCV maturation.","method":"Proteomic analysis of purified LCVs, in vitro LCV aggregation assay with GTP/GDP, dominant-negative mutant expression, siRNA knockdown, fluorescence and electron microscopy","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution assay with nucleotide specificity, dominant-negative mutant, and KD with defined phenotype in multiple methods","pmids":["28835546"],"is_preprint":false},{"year":2018,"finding":"ATL3/Sey1 controls circumferential ER remodeling around the Legionella-containing vacuole. A dominant-negative Sey1_K154A mutant compromises ER accumulation on LCVs and causes aberrant ER morphology.","method":"Fluorescence microscopy and electron microscopy of infected D. discoideum, dominant-negative mutant expression","journal":"Communicative & integrative biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative mutant with ultrastructural validation, single lab extending prior EMBO reports work","pmids":["30083282"],"is_preprint":false},{"year":2018,"finding":"Lunapark (Lnp) localization to three-way ER junctions is dependent on ATL activity. Reintroduction of ATL1 R77A and ATL3 (which cluster at junctions) relocates Lnp to junctions, while wild-type ATL1 does not. Purified Lnp N-terminus inhibits ATL-mediated vesicle fusion in vitro, suggesting Lnp limits further ATL activity after junction formation.","method":"Deletion/mutation analysis, in vitro vesicle fusion assay with purified proteins, immunofluorescence, ATL KO cell rescue","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified Lnp-NT inhibiting ATL fusion, complemented by cellular localization studies","pmids":["30498943"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of ATL1 and ATL3 reveal the N-terminal hypervariable region (HVR) as an isoform-specific structural feature. The HVR of ATL1 positively affects membrane tethering and cellular ATL1 function, and is post-translationally regulated through phosphorylation. A kinase screen identified candidates that specifically modify this HVR site.","method":"X-ray crystallography of ATL1 and ATL3, in vitro membrane tethering assays, kinase screen, phosphorylation site mapping in cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of both isoforms with functional tethering assays and PTM identification, multiple orthogonal methods","pmids":["34546351"],"is_preprint":false},{"year":2011,"finding":"ATL3 physically associates with STAT5a and STAT5b in cross-immunopanning assays. Upon STAT5a/b knockdown, ATL3 accumulates at cyst-zone boundaries of cystic ER, and ATL3 siRNA leads to effacement of these cyst-zone boundaries, indicating ATL3 is required to maintain the boundaries of the cystic ER phenotype.","method":"Magnetic-bead cross-immunopanning, siRNA knockdown, immunofluorescence microscopy","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP/immunopanning method with complementary KD phenotype, single lab replicated in two papers","pmids":["22159083","23151802"],"is_preprint":false},{"year":2023,"finding":"Coronavirus ORF8 protein binds ATL3 (and FAM134B) and sequesters them into ORF8/p62 liquid droplets/condensates, inhibiting ER-phagy. This ER-phagy inhibition facilitates viral double-membrane vesicle (DMV) formation and activates ER stress.","method":"Co-immunoprecipitation, condensate/liquid droplet assays, ER-phagy flux assays, viral replication measurements, electron microscopy of DMVs","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, condensate formation, and functional ER-phagy assay in single lab with multiple orthogonal methods","pmids":["36952345"],"is_preprint":false},{"year":2023,"finding":"UVRAG localizes to ER-phagy sites upon starvation and interacts with ER-phagy cargo receptors including ATL3. UVRAG regulates oligomerization of cargo receptors and facilitates recruitment of Atg8 family proteins, promoting efficient ER-phagy site assembly and ER turnover.","method":"Co-immunoprecipitation, fluorescence microscopy, oligomerization assays, ER-phagy flux assays, gene knockdown","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with functional assays, single lab, multiple methods","pmids":["37902287"],"is_preprint":false},{"year":2023,"finding":"ATL3 is recruited to ER foci induced by simian virus 40 (SV40) during non-enveloped virus entry. ATL3 deploys its GTPase-dependent membrane fusion activity to promote formation of multi-tubular ER junctions within ER foci that serve as membrane penetration sites for SV40. ATL3 also engages the SV40-containing membrane penetration complex.","method":"Fluorescence and electron microscopy, ATL3 knockdown, dominant-negative GTPase mutant, co-immunoprecipitation with viral complex","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined phenotype plus dominant-negative mutant and Co-IP with viral complex, single lab","pmids":["37578227"],"is_preprint":false},{"year":2025,"finding":"ATL3, together with RTN3L, shapes an ER tubulovesicular structure called the ER tubular body (ER-TB) under cellular stress. ER-TB formation mediates Golgi-independent unconventional protein secretion (UPS) of transmembrane proteins such as ΔF508-CFTR and SARS-CoV-2 spike protein. Individual knockdown of ATL3 inhibits ER-TB formation and UPS; combined supplementation of ATL3 and RTN3L induces ER-TB formation.","method":"Correlative light-electron microscopy, gene knockdown, overexpression, UPS assays for ΔF508-CFTR and spike protein trafficking","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CLEM with functional UPS assays, KD and OE both tested, multiple cargo proteins, single lab with multiple orthogonal methods","pmids":["39919755"],"is_preprint":false},{"year":2024,"finding":"RTN3L and ATL3 are both required for the formation of RTN3L-containing ER-phagy sites (ERPHS), while CALCOCO1 is not. ATL3 targets misfolded, aggregation-prone disease-causing proteins (same substrates as RTN3L) for autophagy, working in parallel with RTN3L and CALCOCO1 at different tubular ER sites.","method":"Colocalization microscopy, siRNA knockdown of individual receptors, autophagy flux assays with misfolded protein substrates","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD studies with colocalization, functional substrate clearance assay, single lab","pmids":["38818751"],"is_preprint":false},{"year":2025,"finding":"ATL3, together with RTN3L and LNP (LNPK), is required for the formation of ER foci that sequester misassembled FG-rich nucleoporins (FG-Nups). Preventing this sequestration impairs NPC nucleo-cytoplasmic transport, suggesting ATL3 participates in an ER-based quality control mechanism for misassembled nuclear pore components.","method":"siRNA/shRNA knockdown of RTN3, ATL3, and LNP, immunofluorescence, nuclear transport assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD of multiple ER morphogenic proteins with defined functional transport phenotype, single lab","pmids":["40079246"],"is_preprint":false}],"current_model":"ATL3 is a dynamin-like GTPase resident in the tubular ER network that performs at least two major functions: (1) it mediates GTP hydrolysis-driven homotypic ER membrane fusion at three-way junctions (with a crystal-structure-defined catalytic mechanism and an isoform-specific N-terminal hypervariable region subject to phospho-regulation), and (2) it acts as a selective ER-phagy receptor by directly binding GABARAP subfamily proteins via two GIM motifs to drive lysosomal degradation of tubular ER; disease-causing mutations (Y192C, P338R) abolish the GABARAP interaction, disrupt ER junction morphology, increase ER-mitochondria contacts, and impair axonal function, while ATL3 is additionally hijacked by multiple viruses (coronavirus ORF8/p62 condensates, ZIKV replication complexes, SV40 entry foci) to subvert or exploit ER membrane dynamics."},"narrative":{"mechanistic_narrative":"ATL3 is a dynamin-like GTPase of the tubular endoplasmic reticulum that drives homotypic ER membrane fusion to build and maintain the polygonal ER network, and additionally functions as a selective ER-phagy receptor [PMID:30773365, PMID:27669642]. Loss of all three atlastins abolishes the formation of three-way ER tubule junctions, a defect rescuable by any single atlastin or distant orthologs, establishing ATL3 within a redundant machinery essential for the polygonal ER [PMID:27669642]; crystallographic and biochemical analysis defines its catalytic cycle of nucleotide binding, dimerization, hydrolysis, and Mg2+ displacement to reset the enzyme, and an isoform-specific N-terminal hypervariable region subject to phospho-regulation [PMID:28602821, PMID:34546351]. Its fusion activity is restrained downstream by Lunapark, which localizes to junctions in an ATL-dependent manner and inhibits further ATL-mediated fusion in vitro [PMID:30498943]. As an ER-phagy receptor, ATL3 selectively binds GABARAP-subfamily Atg8 proteins (but not LC3) through two GABARAP-interaction motifs to target tubular ER for starvation-induced lysosomal degradation, with UVRAG promoting cargo-receptor oligomerization and Atg8 recruitment at ER-phagy sites [PMID:30773365, PMID:37902287]; ATL3 acts in parallel with RTN3L to clear misfolded, aggregation-prone substrates and to sequester misassembled FG-nucleoporins as a form of ER quality control [PMID:38818751, PMID:40079246], and partners with RTN3L to form ER tubular bodies that mediate Golgi-independent unconventional secretion of transmembrane cargo [PMID:39919755]. The HSAN I mutations Y192C and P338R abolish GABARAP binding and ER-phagy, mislocalize ATL3 from junctions, disrupt tubular ER and Golgi morphology, increase ER-mitochondria contacts, and impair axonal growth and mitochondrial transport, linking defective ER dynamics and ER-phagy to peripheral neuropathy [PMID:30773365, PMID:30680846, PMID:24459106, PMID:30666337, PMID:30339187]. ATL3 is exploited by multiple pathogens: it is recruited to Zika virus replication complexes via NS2A/NS2B3 and to SV40 entry foci, supports Legionella-containing vacuole expansion through GTP-dependent membrane remodeling, and is sequestered by coronavirus ORF8/p62 condensates to suppress ER-phagy and promote viral double-membrane vesicle formation [PMID:31534046, PMID:28835546, PMID:36952345, PMID:37578227].","teleology":[{"year":2011,"claim":"Early evidence connected ATL3 to maintenance of distinct ER subdomains by showing it associates with STAT5 and is required to maintain cystic ER boundaries, hinting at a structural ER-shaping role before its enzymology was defined.","evidence":"Cross-immunopanning and siRNA knockdown with fluorescence microscopy","pmids":["22159083","23151802"],"confidence":"Medium","gaps":["Mechanistic link between STAT5 binding and ER morphology unresolved","Single immunopanning method without reciprocal biochemical validation of the interaction"]},{"year":2014,"claim":"Localization studies established ATL3 as a junction-enriched ER GTPase and showed the HSAN I mutation Y192C mislocalizes it and disrupts tubular ER, framing a dominant-negative morphological disease mechanism.","evidence":"Immunofluorescence of wild-type and mutant ATL3 in cells and patient samples","pmids":["24459106"],"confidence":"High","gaps":["Did not define the catalytic basis of fusion","Did not establish whether the morphology defect is causal for neuropathy"]},{"year":2016,"claim":"CRISPR triple knockout of all atlastins resolved whether ATL3 is necessary for ER network architecture, showing atlastins are collectively required for three-way junction formation and functionally interchangeable with distant orthologs.","evidence":"Atl1/2/3 triple knockout NIH-3T3 cells with ortholog rescue and ER morphology imaging","pmids":["27669642"],"confidence":"High","gaps":["Redundancy obscures ATL3-specific contributions","Did not address isoform-specific functions or regulation"]},{"year":2017,"claim":"Crystal structures of ATL3 captured discrete catalytic intermediates, establishing the molecular mechanism of its GTPase cycle including Mg2+ displacement to reset the enzyme for repeated fusion.","evidence":"X-ray crystallography with comparative ATL1/ATL3 GTPase biochemistry","pmids":["28602821"],"confidence":"High","gaps":["Structures of full fusion intermediates on membranes not resolved","Functional difference between ATL1 and ATL3 isoforms not defined here"]},{"year":2017,"claim":"Work on Legionella showed ATL3/Sey1 is hijacked for pathogen vacuole biogenesis, with in vitro reconstitution demonstrating GTP-specific membrane aggregation, extending ATL3's fusion activity to a host-pathogen context.","evidence":"LCV proteomics, in vitro GTP/GDP aggregation assay, dominant-negative mutant and knockdown","pmids":["28835546"],"confidence":"High","gaps":["Direct role in mammalian infection versus model amoeba not delineated","How the pathogen recruits ATL3 is unknown"]},{"year":2018,"claim":"Lunapark was placed downstream of ATL activity, showing ATL3 controls Lnp junction localization while Lnp in turn limits further ATL-mediated fusion, defining a feedback that stabilizes junctions.","evidence":"Mutation analysis, in vitro vesicle fusion with purified Lnp N-terminus, ATL KO rescue","pmids":["30498943"],"confidence":"High","gaps":["Stoichiometry and dynamics of the ATL3-Lnp feedback in cells not quantified"]},{"year":2019,"claim":"ATL3 was identified as a selective tubular ER-phagy receptor binding GABARAP-subfamily proteins through two GIMs, defining a degradative function distinct from its fusion role and explaining starvation-induced ER turnover.","evidence":"Reciprocal Co-IP, GIM binding assays, starvation autophagy flux and microscopy","pmids":["30773365"],"confidence":"High","gaps":["Selectivity for GABARAP over LC3 mechanism not fully resolved","Regulation of switching between fusion and ER-phagy functions unknown"]},{"year":2019,"claim":"The HSAN I mutations were mechanistically tied to ER-phagy and broad organelle dysfunction, showing Y192C and P338R abolish GABARAP binding, disrupt ER/Golgi/nuclear morphology, increase ER-mitochondria contacts, and impair axonal growth and mitochondrial transport.","evidence":"Mutant expression in cells and primary neurons, patient fibroblasts, EM of contact sites, Ca2+ imaging, autophagy and axon assays","pmids":["30773365","30680846","30666337","30339187"],"confidence":"High","gaps":["Which downstream defect is the primary driver of neuropathy not established","Relative contributions of lost fusion versus lost ER-phagy not separated"]},{"year":2019,"claim":"ATL3 was shown to be co-opted by Zika virus, binding NS2A/NS2B3 and supporting replication, extending pathogen exploitation of ATL3 ER dynamics to a flavivirus.","evidence":"Co-IP with viral proteins, siRNA knockdown, colocalization at replication sites, viral titers","pmids":["31534046"],"confidence":"Medium","gaps":["Whether fusion or ER-phagy activity is the relevant function for ZIKV unclear","Single lab without reciprocal interaction validation"]},{"year":2021,"claim":"Structures of both ATL1 and ATL3 defined the N-terminal hypervariable region as an isoform-specific, phospho-regulated element affecting membrane tethering, providing a basis for differential regulation of atlastin paralogs.","evidence":"X-ray crystallography of ATL1/ATL3, in vitro tethering assays, kinase screen and PTM mapping","pmids":["34546351"],"confidence":"High","gaps":["Functional consequence of ATL3 HVR phosphorylation specifically not detailed","Physiological kinase for the site not validated"]},{"year":2023,"claim":"ATL3's ER-phagy receptor activity was shown to be a viral target, with coronavirus ORF8 sequestering ATL3 into p62 condensates to inhibit ER-phagy and promote double-membrane vesicle formation.","evidence":"Co-IP, condensate assays, ER-phagy flux, viral replication and DMV electron microscopy","pmids":["36952345"],"confidence":"Medium","gaps":["Direct versus indirect ATL3-ORF8 binding within condensates not separated","Single lab"]},{"year":2023,"claim":"UVRAG was identified as a regulator of ER-phagy that interacts with ATL3 and promotes cargo-receptor oligomerization and Atg8 recruitment, placing ATL3 in a larger assembly mechanism for ER-phagy sites.","evidence":"Co-IP, oligomerization and ER-phagy flux assays, knockdown, microscopy","pmids":["37902287"],"confidence":"Medium","gaps":["Whether UVRAG acts specifically on ATL3 versus multiple receptors not resolved","Single lab"]},{"year":2023,"claim":"ATL3's GTPase-dependent fusion was shown to build multi-tubular ER junctions at SV40 entry foci, demonstrating that a non-enveloped virus exploits ATL3 membrane remodeling for cell entry.","evidence":"Fluorescence and electron microscopy, knockdown, dominant-negative GTPase mutant, Co-IP with viral penetration complex","pmids":["37578227"],"confidence":"Medium","gaps":["Mechanism by which ATL3 engages the penetration complex not defined","Single lab"]},{"year":2024,"claim":"ATL3 was shown to act with RTN3L at dedicated ER-phagy sites to clear aggregation-prone misfolded proteins, distinguishing parallel tubular ER-phagy pathways and defining ATL3 substrates.","evidence":"Colocalization microscopy, individual receptor knockdowns, autophagy flux with misfolded substrates","pmids":["38818751"],"confidence":"Medium","gaps":["How substrate selectivity between parallel receptors is achieved unknown","Single lab"]},{"year":2025,"claim":"ATL3 was implicated in two further ER-shaping functions: with RTN3L it forms ER tubular bodies mediating Golgi-independent unconventional secretion, and with RTN3L/LNP it sequesters misassembled FG-nucleoporins as ER-based quality control.","evidence":"Correlative light-electron microscopy, knockdown/overexpression, UPS assays and nuclear transport assays","pmids":["39919755","40079246"],"confidence":"High","gaps":["How ATL3 fusion activity is repurposed toward secretory tubular bodies versus degradation unclear","Mechanism of nucleoporin sequestration not resolved"]},{"year":null,"claim":"It remains unknown how ATL3 is molecularly switched between its membrane-fusion, ER-phagy, unconventional-secretion, and quality-control roles, and which single downstream defect drives HSAN I pathology.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No defined regulatory mechanism partitioning ATL3 among its functions","Causal hierarchy of mutant phenotypes in neuropathy unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[2,3,8,11,15]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,14,17]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,4,5,16]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,14,17]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,10,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,7,13,15]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[16]}],"complexes":[],"partners":["GABARAP","LNPK","RTN3L","UVRAG","STAT5A","STAT5B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6DD88","full_name":"Atlastin-3","aliases":[],"length_aa":541,"mass_kda":60.5,"function":"Atlastin-3 (ATL3) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network. It facilitates the formation of three-way junctions where ER tubules intersect (PubMed:18270207, PubMed:19665976, PubMed:24459106, PubMed:27619977, PubMed:37102997). Two atlastin-3 on neighboring ER tubules bind GTP and form loose homodimers through the GB1/RHD3-type G domains and 3HB regions. Upon GTP hydrolysis, the 3HB regions tighten, pulling the membranes together to drive their fusion. After fusion, the homodimer disassembles upon release of inorganic phosphate (Pi). Subsequently, GDP dissociates, resetting the monomers to a conformation ready for a new fusion cycle (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q6DD88/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATL3","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000184743","cell_line_id":"CID000367","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"ATL2","stoichiometry":4.0},{"gene":"REEP5","stoichiometry":4.0},{"gene":"RTN3","stoichiometry":4.0},{"gene":"RTN4","stoichiometry":4.0},{"gene":"TAF12","stoichiometry":4.0},{"gene":"ARL6IP1","stoichiometry":0.2},{"gene":"NRBF2","stoichiometry":0.2},{"gene":"ATL1","stoichiometry":0.2},{"gene":"GRWD1","stoichiometry":0.2},{"gene":"ESYT1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000367","total_profiled":1310},"omim":[{"mim_id":"615632","title":"NEUROPATHY, HEREDITARY SENSORY, TYPE IF; HSN1F","url":"https://www.omim.org/entry/615632"},{"mim_id":"610243","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 27; ZFYVE27","url":"https://www.omim.org/entry/610243"},{"mim_id":"609369","title":"ATLASTIN GTPase 3; ATL3","url":"https://www.omim.org/entry/609369"},{"mim_id":"162400","title":"NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IA; HSAN1A","url":"https://www.omim.org/entry/162400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATL3"},"hgnc":{"alias_symbol":["DKFZP564J0863"],"prev_symbol":[]},"alphafold":{"accession":"Q6DD88","domains":[{"cath_id":"3.40.50.300","chopping":"24-341","consensus_level":"high","plddt":91.127,"start":24,"end":341},{"cath_id":"1.20.58.420","chopping":"345-440","consensus_level":"medium","plddt":90.0494,"start":345,"end":440},{"cath_id":"-","chopping":"442-516","consensus_level":"medium","plddt":85.5191,"start":442,"end":516}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6DD88","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6DD88-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6DD88-F1-predicted_aligned_error_v6.png","plddt_mean":86.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATL3","jax_strain_url":"https://www.jax.org/strain/search?query=ATL3"},"sequence":{"accession":"Q6DD88","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6DD88.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6DD88/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6DD88"}},"corpus_meta":[{"pmid":"30773365","id":"PMC_30773365","title":"ATL3 Is a Tubular ER-Phagy Receptor for GABARAP-Mediated Selective Autophagy.","date":"2019","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/30773365","citation_count":251,"is_preprint":false},{"pmid":"33111629","id":"PMC_33111629","title":"ATF4 links ER stress with reticulophagy in glioblastoma cells.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/33111629","citation_count":123,"is_preprint":false},{"pmid":"35127371","id":"PMC_35127371","title":"Therapeutic regulation of autophagy in hepatic metabolism.","date":"2021","source":"Acta pharmaceutica Sinica. 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This interaction is essential for ATL3-mediated selective autophagy of tubular ER upon starvation.\",\n      \"method\": \"Co-immunoprecipitation, binding assays, starvation-induced autophagy assays, fluorescence microscopy\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying specific binding partners, functional validation with loss-of-function, independently corroborated by multiple subsequent studies\",\n      \"pmids\": [\"30773365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HSAN I-associated ATL3 mutations Y192C and P338R disrupt ATL3's association with GABARAP and impair ATL3's function in ER-phagy, linking defective ER-phagy to the disease mechanism.\",\n      \"method\": \"Co-immunoprecipitation with mutant constructs, autophagy flux assays in cells expressing disease mutants\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutant-specific Co-IP and functional autophagy assay, replicated in disease patient context by independent studies\",\n      \"pmids\": [\"30773365\", \"30680846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ATL3 is a dynamin-like GTPase enriched at three-way junctions of the tubular ER network. The disease-causing mutation p.Tyr192Cys causes mutant ATL3 to fail to localize to branch points and instead disrupts the tubular ER structure, suggesting a dominant-negative effect on ER morphology.\",\n      \"method\": \"Immunofluorescence microscopy of wild-type and mutant ATL3 localization in cells, patient-derived samples\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence, replicated across multiple subsequent studies with the same mutation\",\n      \"pmids\": [\"24459106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of ATL3 reveals discrete temporal steps in the GTPase catalytic cycle, including nucleotide binding, hydrolysis, ATL dimerization, and phosphate release. The structure suggests a mechanism for displacement of the catalytic Mg2+ ion following GTP hydrolysis to reset the cycle.\",\n      \"method\": \"X-ray crystallography, biochemical GTPase assays comparing ATL1 and ATL3 isoforms\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biochemical functional validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28602821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Triple knockout of all three atlastins (Atl1/2/3) in mammalian NIH-3T3 cells using CRISPR/Cas9 markedly disrupts ER morphology, specifically impairing formation of three-way ER tubule junctions. This phenotype can be rescued by any single human atlastin or distant orthologs (Sey1p, RHD3), establishing atlastins as necessary for polygonal ER network formation.\",\n      \"method\": \"CRISPR/Cas9 knockout, rescue experiments with heterologous orthologs, fluorescence microscopy of ER morphology\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype and rescue experiments with multiple orthologs, multiple orthogonal methods\",\n      \"pmids\": [\"27669642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATL3 mutation Y192C reduces the complexity of the tubular ER network, delays ER export by reducing the number of ER exit sites, reduces autophagy, fragments the Golgi, and causes nuclear malformation. In primary neurons, ATL3 Y192C does not localize to the growing axon, resulting in axon growth deficits.\",\n      \"method\": \"Expression of disease mutant in cultured cells and primary neurons, patient-derived fibroblasts, immunofluorescence, autophagosome quantification\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ER exit site counting, Golgi morphology, nuclear shape, axon growth) in both cell lines and patient-derived fibroblasts\",\n      \"pmids\": [\"30666337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Disease-causing ATL3 mutations (Y192C and P338R) increase the number of ER-mitochondria contact sites in HeLa cells and patient-derived fibroblasts, reflected in higher phospholipid metabolism, upregulated autophagy, augmented Ca2+ crosstalk between ER and mitochondria, and decreased mitochondrial motility. Neurons expressing these mutations show strongly decreased numbers of axonal mitochondria.\",\n      \"method\": \"Electron microscopy of ER-mitochondria contacts, Ca2+ imaging, mitochondrial motility tracking, phospholipid analysis, patient-derived fibroblasts, neuronal culture\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EM, Ca2+ imaging, lipid analysis, live imaging) in both cell lines and patient cells\",\n      \"pmids\": [\"30339187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATL3 interacts with Zika virus nonstructural proteins NS2A and NS2B3, is recruited to viral replication sites, and is required for efficient ZIKV replication. Depletion of ATL proteins significantly decreased intracellular viral protein levels and released virus.\",\n      \"method\": \"Co-immunoprecipitation of ATL3 with viral NS2A/NS2B3, siRNA knockdown, immunofluorescence colocalization at replication sites, viral titer measurements\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and colocalization at replication sites with KD phenotype, single lab\",\n      \"pmids\": [\"31534046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Atlastin3 (Atl3/Sey1p) localizes to early Legionella-containing vacuoles (LCVs) and is critical for LCV expansion and pathogen replication. GTP (but not GDP) catalyzes Sey1-dependent aggregation of purified ER-positive LCVs in vitro. A catalytically inactive dominant-negative GTPase mutant or ATL3 depletion restricts replication and impairs LCV maturation.\",\n      \"method\": \"Proteomic analysis of purified LCVs, in vitro LCV aggregation assay with GTP/GDP, dominant-negative mutant expression, siRNA knockdown, fluorescence and electron microscopy\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution assay with nucleotide specificity, dominant-negative mutant, and KD with defined phenotype in multiple methods\",\n      \"pmids\": [\"28835546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATL3/Sey1 controls circumferential ER remodeling around the Legionella-containing vacuole. A dominant-negative Sey1_K154A mutant compromises ER accumulation on LCVs and causes aberrant ER morphology.\",\n      \"method\": \"Fluorescence microscopy and electron microscopy of infected D. discoideum, dominant-negative mutant expression\",\n      \"journal\": \"Communicative & integrative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative mutant with ultrastructural validation, single lab extending prior EMBO reports work\",\n      \"pmids\": [\"30083282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Lunapark (Lnp) localization to three-way ER junctions is dependent on ATL activity. Reintroduction of ATL1 R77A and ATL3 (which cluster at junctions) relocates Lnp to junctions, while wild-type ATL1 does not. Purified Lnp N-terminus inhibits ATL-mediated vesicle fusion in vitro, suggesting Lnp limits further ATL activity after junction formation.\",\n      \"method\": \"Deletion/mutation analysis, in vitro vesicle fusion assay with purified proteins, immunofluorescence, ATL KO cell rescue\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified Lnp-NT inhibiting ATL fusion, complemented by cellular localization studies\",\n      \"pmids\": [\"30498943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of ATL1 and ATL3 reveal the N-terminal hypervariable region (HVR) as an isoform-specific structural feature. The HVR of ATL1 positively affects membrane tethering and cellular ATL1 function, and is post-translationally regulated through phosphorylation. A kinase screen identified candidates that specifically modify this HVR site.\",\n      \"method\": \"X-ray crystallography of ATL1 and ATL3, in vitro membrane tethering assays, kinase screen, phosphorylation site mapping in cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of both isoforms with functional tethering assays and PTM identification, multiple orthogonal methods\",\n      \"pmids\": [\"34546351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATL3 physically associates with STAT5a and STAT5b in cross-immunopanning assays. Upon STAT5a/b knockdown, ATL3 accumulates at cyst-zone boundaries of cystic ER, and ATL3 siRNA leads to effacement of these cyst-zone boundaries, indicating ATL3 is required to maintain the boundaries of the cystic ER phenotype.\",\n      \"method\": \"Magnetic-bead cross-immunopanning, siRNA knockdown, immunofluorescence microscopy\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP/immunopanning method with complementary KD phenotype, single lab replicated in two papers\",\n      \"pmids\": [\"22159083\", \"23151802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Coronavirus ORF8 protein binds ATL3 (and FAM134B) and sequesters them into ORF8/p62 liquid droplets/condensates, inhibiting ER-phagy. This ER-phagy inhibition facilitates viral double-membrane vesicle (DMV) formation and activates ER stress.\",\n      \"method\": \"Co-immunoprecipitation, condensate/liquid droplet assays, ER-phagy flux assays, viral replication measurements, electron microscopy of DMVs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, condensate formation, and functional ER-phagy assay in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36952345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UVRAG localizes to ER-phagy sites upon starvation and interacts with ER-phagy cargo receptors including ATL3. UVRAG regulates oligomerization of cargo receptors and facilitates recruitment of Atg8 family proteins, promoting efficient ER-phagy site assembly and ER turnover.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy, oligomerization assays, ER-phagy flux assays, gene knockdown\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with functional assays, single lab, multiple methods\",\n      \"pmids\": [\"37902287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATL3 is recruited to ER foci induced by simian virus 40 (SV40) during non-enveloped virus entry. ATL3 deploys its GTPase-dependent membrane fusion activity to promote formation of multi-tubular ER junctions within ER foci that serve as membrane penetration sites for SV40. ATL3 also engages the SV40-containing membrane penetration complex.\",\n      \"method\": \"Fluorescence and electron microscopy, ATL3 knockdown, dominant-negative GTPase mutant, co-immunoprecipitation with viral complex\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined phenotype plus dominant-negative mutant and Co-IP with viral complex, single lab\",\n      \"pmids\": [\"37578227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATL3, together with RTN3L, shapes an ER tubulovesicular structure called the ER tubular body (ER-TB) under cellular stress. ER-TB formation mediates Golgi-independent unconventional protein secretion (UPS) of transmembrane proteins such as ΔF508-CFTR and SARS-CoV-2 spike protein. Individual knockdown of ATL3 inhibits ER-TB formation and UPS; combined supplementation of ATL3 and RTN3L induces ER-TB formation.\",\n      \"method\": \"Correlative light-electron microscopy, gene knockdown, overexpression, UPS assays for ΔF508-CFTR and spike protein trafficking\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLEM with functional UPS assays, KD and OE both tested, multiple cargo proteins, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39919755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RTN3L and ATL3 are both required for the formation of RTN3L-containing ER-phagy sites (ERPHS), while CALCOCO1 is not. ATL3 targets misfolded, aggregation-prone disease-causing proteins (same substrates as RTN3L) for autophagy, working in parallel with RTN3L and CALCOCO1 at different tubular ER sites.\",\n      \"method\": \"Colocalization microscopy, siRNA knockdown of individual receptors, autophagy flux assays with misfolded protein substrates\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD studies with colocalization, functional substrate clearance assay, single lab\",\n      \"pmids\": [\"38818751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATL3, together with RTN3L and LNP (LNPK), is required for the formation of ER foci that sequester misassembled FG-rich nucleoporins (FG-Nups). Preventing this sequestration impairs NPC nucleo-cytoplasmic transport, suggesting ATL3 participates in an ER-based quality control mechanism for misassembled nuclear pore components.\",\n      \"method\": \"siRNA/shRNA knockdown of RTN3, ATL3, and LNP, immunofluorescence, nuclear transport assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD of multiple ER morphogenic proteins with defined functional transport phenotype, single lab\",\n      \"pmids\": [\"40079246\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATL3 is a dynamin-like GTPase resident in the tubular ER network that performs at least two major functions: (1) it mediates GTP hydrolysis-driven homotypic ER membrane fusion at three-way junctions (with a crystal-structure-defined catalytic mechanism and an isoform-specific N-terminal hypervariable region subject to phospho-regulation), and (2) it acts as a selective ER-phagy receptor by directly binding GABARAP subfamily proteins via two GIM motifs to drive lysosomal degradation of tubular ER; disease-causing mutations (Y192C, P338R) abolish the GABARAP interaction, disrupt ER junction morphology, increase ER-mitochondria contacts, and impair axonal function, while ATL3 is additionally hijacked by multiple viruses (coronavirus ORF8/p62 condensates, ZIKV replication complexes, SV40 entry foci) to subvert or exploit ER membrane dynamics.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATL3 is a dynamin-like GTPase of the tubular endoplasmic reticulum that drives homotypic ER membrane fusion to build and maintain the polygonal ER network, and additionally functions as a selective ER-phagy receptor [#0, #4]. Loss of all three atlastins abolishes the formation of three-way ER tubule junctions, a defect rescuable by any single atlastin or distant orthologs, establishing ATL3 within a redundant machinery essential for the polygonal ER [#4]; crystallographic and biochemical analysis defines its catalytic cycle of nucleotide binding, dimerization, hydrolysis, and Mg2+ displacement to reset the enzyme, and an isoform-specific N-terminal hypervariable region subject to phospho-regulation [#3, #11]. Its fusion activity is restrained downstream by Lunapark, which localizes to junctions in an ATL-dependent manner and inhibits further ATL-mediated fusion in vitro [#10]. As an ER-phagy receptor, ATL3 selectively binds GABARAP-subfamily Atg8 proteins (but not LC3) through two GABARAP-interaction motifs to target tubular ER for starvation-induced lysosomal degradation, with UVRAG promoting cargo-receptor oligomerization and Atg8 recruitment at ER-phagy sites [#0, #14]; ATL3 acts in parallel with RTN3L to clear misfolded, aggregation-prone substrates and to sequester misassembled FG-nucleoporins as a form of ER quality control [#17, #18], and partners with RTN3L to form ER tubular bodies that mediate Golgi-independent unconventional secretion of transmembrane cargo [#16]. The HSAN I mutations Y192C and P338R abolish GABARAP binding and ER-phagy, mislocalize ATL3 from junctions, disrupt tubular ER and Golgi morphology, increase ER-mitochondria contacts, and impair axonal growth and mitochondrial transport, linking defective ER dynamics and ER-phagy to peripheral neuropathy [#1, #2, #5, #6]. ATL3 is exploited by multiple pathogens: it is recruited to Zika virus replication complexes via NS2A/NS2B3 and to SV40 entry foci, supports Legionella-containing vacuole expansion through GTP-dependent membrane remodeling, and is sequestered by coronavirus ORF8/p62 condensates to suppress ER-phagy and promote viral double-membrane vesicle formation [#7, #8, #13, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Early evidence connected ATL3 to maintenance of distinct ER subdomains by showing it associates with STAT5 and is required to maintain cystic ER boundaries, hinting at a structural ER-shaping role before its enzymology was defined.\",\n      \"evidence\": \"Cross-immunopanning and siRNA knockdown with fluorescence microscopy\",\n      \"pmids\": [\"22159083\", \"23151802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between STAT5 binding and ER morphology unresolved\", \"Single immunopanning method without reciprocal biochemical validation of the interaction\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Localization studies established ATL3 as a junction-enriched ER GTPase and showed the HSAN I mutation Y192C mislocalizes it and disrupts tubular ER, framing a dominant-negative morphological disease mechanism.\",\n      \"evidence\": \"Immunofluorescence of wild-type and mutant ATL3 in cells and patient samples\",\n      \"pmids\": [\"24459106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the catalytic basis of fusion\", \"Did not establish whether the morphology defect is causal for neuropathy\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CRISPR triple knockout of all atlastins resolved whether ATL3 is necessary for ER network architecture, showing atlastins are collectively required for three-way junction formation and functionally interchangeable with distant orthologs.\",\n      \"evidence\": \"Atl1/2/3 triple knockout NIH-3T3 cells with ortholog rescue and ER morphology imaging\",\n      \"pmids\": [\"27669642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy obscures ATL3-specific contributions\", \"Did not address isoform-specific functions or regulation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Crystal structures of ATL3 captured discrete catalytic intermediates, establishing the molecular mechanism of its GTPase cycle including Mg2+ displacement to reset the enzyme for repeated fusion.\",\n      \"evidence\": \"X-ray crystallography with comparative ATL1/ATL3 GTPase biochemistry\",\n      \"pmids\": [\"28602821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of full fusion intermediates on membranes not resolved\", \"Functional difference between ATL1 and ATL3 isoforms not defined here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Work on Legionella showed ATL3/Sey1 is hijacked for pathogen vacuole biogenesis, with in vitro reconstitution demonstrating GTP-specific membrane aggregation, extending ATL3's fusion activity to a host-pathogen context.\",\n      \"evidence\": \"LCV proteomics, in vitro GTP/GDP aggregation assay, dominant-negative mutant and knockdown\",\n      \"pmids\": [\"28835546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct role in mammalian infection versus model amoeba not delineated\", \"How the pathogen recruits ATL3 is unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Lunapark was placed downstream of ATL activity, showing ATL3 controls Lnp junction localization while Lnp in turn limits further ATL-mediated fusion, defining a feedback that stabilizes junctions.\",\n      \"evidence\": \"Mutation analysis, in vitro vesicle fusion with purified Lnp N-terminus, ATL KO rescue\",\n      \"pmids\": [\"30498943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of the ATL3-Lnp feedback in cells not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ATL3 was identified as a selective tubular ER-phagy receptor binding GABARAP-subfamily proteins through two GIMs, defining a degradative function distinct from its fusion role and explaining starvation-induced ER turnover.\",\n      \"evidence\": \"Reciprocal Co-IP, GIM binding assays, starvation autophagy flux and microscopy\",\n      \"pmids\": [\"30773365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity for GABARAP over LC3 mechanism not fully resolved\", \"Regulation of switching between fusion and ER-phagy functions unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The HSAN I mutations were mechanistically tied to ER-phagy and broad organelle dysfunction, showing Y192C and P338R abolish GABARAP binding, disrupt ER/Golgi/nuclear morphology, increase ER-mitochondria contacts, and impair axonal growth and mitochondrial transport.\",\n      \"evidence\": \"Mutant expression in cells and primary neurons, patient fibroblasts, EM of contact sites, Ca2+ imaging, autophagy and axon assays\",\n      \"pmids\": [\"30773365\", \"30680846\", \"30666337\", \"30339187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which downstream defect is the primary driver of neuropathy not established\", \"Relative contributions of lost fusion versus lost ER-phagy not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ATL3 was shown to be co-opted by Zika virus, binding NS2A/NS2B3 and supporting replication, extending pathogen exploitation of ATL3 ER dynamics to a flavivirus.\",\n      \"evidence\": \"Co-IP with viral proteins, siRNA knockdown, colocalization at replication sites, viral titers\",\n      \"pmids\": [\"31534046\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether fusion or ER-phagy activity is the relevant function for ZIKV unclear\", \"Single lab without reciprocal interaction validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structures of both ATL1 and ATL3 defined the N-terminal hypervariable region as an isoform-specific, phospho-regulated element affecting membrane tethering, providing a basis for differential regulation of atlastin paralogs.\",\n      \"evidence\": \"X-ray crystallography of ATL1/ATL3, in vitro tethering assays, kinase screen and PTM mapping\",\n      \"pmids\": [\"34546351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of ATL3 HVR phosphorylation specifically not detailed\", \"Physiological kinase for the site not validated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"ATL3's ER-phagy receptor activity was shown to be a viral target, with coronavirus ORF8 sequestering ATL3 into p62 condensates to inhibit ER-phagy and promote double-membrane vesicle formation.\",\n      \"evidence\": \"Co-IP, condensate assays, ER-phagy flux, viral replication and DMV electron microscopy\",\n      \"pmids\": [\"36952345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect ATL3-ORF8 binding within condensates not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"UVRAG was identified as a regulator of ER-phagy that interacts with ATL3 and promotes cargo-receptor oligomerization and Atg8 recruitment, placing ATL3 in a larger assembly mechanism for ER-phagy sites.\",\n      \"evidence\": \"Co-IP, oligomerization and ER-phagy flux assays, knockdown, microscopy\",\n      \"pmids\": [\"37902287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether UVRAG acts specifically on ATL3 versus multiple receptors not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"ATL3's GTPase-dependent fusion was shown to build multi-tubular ER junctions at SV40 entry foci, demonstrating that a non-enveloped virus exploits ATL3 membrane remodeling for cell entry.\",\n      \"evidence\": \"Fluorescence and electron microscopy, knockdown, dominant-negative GTPase mutant, Co-IP with viral penetration complex\",\n      \"pmids\": [\"37578227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ATL3 engages the penetration complex not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ATL3 was shown to act with RTN3L at dedicated ER-phagy sites to clear aggregation-prone misfolded proteins, distinguishing parallel tubular ER-phagy pathways and defining ATL3 substrates.\",\n      \"evidence\": \"Colocalization microscopy, individual receptor knockdowns, autophagy flux with misfolded substrates\",\n      \"pmids\": [\"38818751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How substrate selectivity between parallel receptors is achieved unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ATL3 was implicated in two further ER-shaping functions: with RTN3L it forms ER tubular bodies mediating Golgi-independent unconventional secretion, and with RTN3L/LNP it sequesters misassembled FG-nucleoporins as ER-based quality control.\",\n      \"evidence\": \"Correlative light-electron microscopy, knockdown/overexpression, UPS assays and nuclear transport assays\",\n      \"pmids\": [\"39919755\", \"40079246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATL3 fusion activity is repurposed toward secretory tubular bodies versus degradation unclear\", \"Mechanism of nucleoporin sequestration not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how ATL3 is molecularly switched between its membrane-fusion, ER-phagy, unconventional-secretion, and quality-control roles, and which single downstream defect drives HSAN I pathology.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No defined regulatory mechanism partitioning ATL3 among its functions\", \"Causal hierarchy of mutant phenotypes in neuropathy unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [2, 3, 8, 11, 15]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 14, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 4, 5, 16]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 14, 17]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 10, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 7, 13, 15]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GABARAP\", \"LNPK\", \"RTN3L\", \"UVRAG\", \"STAT5A\", \"STAT5B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}