{"gene":"ATL2","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2008,"finding":"ATL2 (atlastin-2) is a large, membrane-bound GTPase localized to the endoplasmic reticulum (ER) in non-neuronal tissues. Knockdown of ATL2 in HeLa cells by siRNA disrupts Golgi morphology, and expression of dominant-negative (GTPase-deficient) atlastin proteins causes prominent inhibition of ER reticularization, specifically blocking formation of three-way junctions in the ER tubular network.","method":"siRNA knockdown in HeLa cells, dominant-negative overexpression, fluorescence microscopy of ER and Golgi morphology","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean siRNA KD plus dominant-negative OE with defined morphological phenotype, single lab, two complementary approaches","pmids":["18270207"],"is_preprint":false},{"year":2016,"finding":"Triple CRISPR/Cas9 knockout of all three atlastins (Atl1/2/3) in NIH-3T3 cells causes marked disruption of ER morphology with prominent impairment of three-way ER tubule junction formation. This phenotype is rescued by re-expression of any single human atlastin (ATL1, ATL2, or ATL3), or distant orthologs from yeast (Sey1p) or Arabidopsis (RHD3), establishing ATL2 as functionally redundant with paralogs in ER network formation. Atlastins are also required for proper adipocyte-like differentiation of NIH-3T3 cells, and their loss alters BMP signaling and increases ER stress sensitivity.","method":"CRISPR/Cas9 triple knockout, rescue expression assays, fluorescence microscopy of ER morphology, differentiation assays","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with multiple orthogonal rescue experiments (three paralogs + two distant orthologs), defined cellular phenotype, rigorous controls","pmids":["27669642"],"is_preprint":false},{"year":2019,"finding":"ATL2 predominantly affects ER morphology by promoting ER tubule fusion (consistent with its GTPase activity), whereas ATL3 has a distinct role as an ER-phagy receptor. ATL2 depletion causes detectable alterations in ER morphology, distinguishing it functionally from ATL3 depletion which barely alters ER morphology.","method":"siRNA depletion, fluorescence microscopy of ER morphology, functional comparison with ATL3","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cited as established prior work within a focused mechanistic study; single lab, morphological readout","pmids":["30773365"],"is_preprint":false},{"year":2021,"finding":"ATL2 GTPase activity is required for normal IP3-induced dendritic Ca2+ signaling in hippocampal neurons. GTPase-deficient ATL2 mutants cause ER morphological alterations, delay the onset and increase the rising time of IP3-evoked Ca2+ signals, and cause RyR2 and IP3R1 channel aggregation and RyR2 redistribution in dendrites.","method":"Expression of GTPase-deficient ATL2 mutants in primary hippocampal neurons, live Ca2+ imaging, fluorescence microscopy of ER morphology and Ca2+ channel distribution","journal":"Cell calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — active-site mutagenesis combined with functional Ca2+ imaging and localization, single lab","pmids":["33812310"],"is_preprint":false},{"year":2022,"finding":"Lunapark (Lnp) ubiquitinates ATL2 at lysines 56, 57, 282, and 302. Lnp localization to ER three-way junctions is required for ATL2 ubiquitination. Expression of an ATL2 ubiquitination-site mutant (K→R substitutions) fails to rescue the decrease in three-way junctions caused by ATL2 knockdown, indicating that Lnp-mediated ubiquitination of ATL2 is required for proper tubular ER network formation.","method":"Co-IP, ubiquitination assays, site-directed mutagenesis, siRNA knockdown, rescue expression, fluorescence microscopy of ER three-way junctions","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical ubiquitination assay with mutagenesis identifying specific sites, functional rescue experiment, single lab with multiple orthogonal methods","pmids":["35894092"],"is_preprint":false},{"year":2019,"finding":"TMCC3 physically binds to atlastins (including ATL2) through its C-terminal transmembrane domains and localizes to ER three-way junctions. TMCC3 knockdown decreases three-way junctions and expands ER sheets; this phenotype is partially rescued by ATL2 overexpression, placing TMCC3 as a positive modulator of atlastin activity at three-way junctions.","method":"Co-IP/binding assays, siRNA knockdown, ATL2 overexpression rescue, fluorescence microscopy of ER morphology","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding assay plus epistatic rescue, single lab, two orthogonal approaches","pmids":["31696206"],"is_preprint":false},{"year":2021,"finding":"ATL2 expression is upregulated by the Alzheimer's disease-linked PS1 M146V mutation and contributes to elevated ER-mitochondria contacts (MAMs). Downregulation of ATL2 after PS1 mutant induction rescued the abnormally elevated ER-mitochondria interactions back to normal levels, identifying ATL2 as a mediator of ER-mitochondria contact sites downstream of mutant presenilin-1.","method":"Comparative hippocampal gene expression profiling, ATL2 siRNA knockdown, ER-mitochondria contact site quantification, Western blotting","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined phenotypic readout (MAM contacts), single lab, supported by in vivo brain expression data","pmids":["34522215"],"is_preprint":false},{"year":2021,"finding":"ATL2 and ATL3 are required for the association of multiple FIP200 autophagosome initiation complexes on the ER surface. Depletion of ATL2/3 impairs the assembly of FIP200 puncta into autophagosome formation sites, placing ATL2 in the pathway linking ER Ca2+ transients to autophagosome initiation.","method":"siRNA depletion, multi-modal SIM analysis, live imaging of FIP200 puncta, epistasis with VAPA/B","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined autophagy initiation phenotype in a high-rigor study, single paper for ATL2-specific role","pmids":["36198318"],"is_preprint":false},{"year":2023,"finding":"ATL2 supports the reticular ER morphology required for the integrity of the ATL3-dependent membrane penetration complex during SV40 (polyomavirus) infection. Unlike ATL3, ATL2 does not reorganize to ER-foci (membrane penetration sites); instead it maintains the overall ER tubular network that is critical for the ATL3-containing complex. ATL2 knockdown impairs SV40 infection.","method":"siRNA knockdown, confocal microscopy, viral infectivity assays, mechanistic comparison with ATL3","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined infectivity phenotype and localization distinction from ATL3, single lab","pmids":["37578227"],"is_preprint":false},{"year":2025,"finding":"ATL2 depletion reduces the spatial distribution of flavivirus (DENV, ZIKV) viral replication organelles (vROs) within infected cells, decreases virus production, and induces innate immune responses. A tethering-competent but fusion-defective ATL2 mutant is sufficient to rescue DENV and ZIKV replication in ATL2-knockout cells, demonstrating that ATL2's membrane-tethering activity (not its fusion activity) is required for vRO organization.","method":"ATL2 knockout, ATL2 tethering/fusion mutant rescue, confocal and electron microscopy, viral replication assays, innate immune response measurement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis separating tethering from fusion activity with functional rescue, preprint not yet peer-reviewed","pmids":["41394679"],"is_preprint":true},{"year":2025,"finding":"ATL2 knockout mice are embryonic lethal with compromised cerebellar development. ATL2 is highly expressed in neuroglia and its loss disorganizes Bergmann glia positioning, interfering with granule cell migration. ATL2-null cells show reduced intracellular membrane area associated with decreased phosphatidylcholine and cholesterol synthesis, indicating ATL2's GTPase-mediated ER fusion activity is required for sustained lipid synthesis and membrane homeostasis.","method":"ATL2 knockout mice, cerebellar histology, glia positioning analysis, lipidomics, membrane area quantification","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with defined developmental phenotype and lipidomics, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.04.12.648519"],"is_preprint":true},{"year":2021,"finding":"A genetic epistasis analysis placing ATL2 within the network of ER-shaping proteins: NOMO1 depletion causes ER morphology collapse, and this was analyzed in the context of known ER-shaping proteins including Atlastin2 and Climp63, establishing ATL2 as part of the functional network maintaining ER structural integrity.","method":"Genetic epistasis analysis, siRNA depletion, electron microscopy of ER morphology","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ATL2 used as epistasis reference rather than direct subject of experiment; single paper, indirect evidence","pmids":["34224731"],"is_preprint":false},{"year":2019,"finding":"miR-30b-5p overexpression in mouse mammary epithelial cells causes downregulation of ATL2 expression, leading to fragmented ER tubular network and increased lipid droplet size, suggesting ATL2 plays a role in lipid droplet formation and ER morphology maintenance in mammary epithelial cells.","method":"Transgenic mouse model with miR-30b-5p overexpression, electron microscopy of ER, lipid droplet quantification, miRNA target validation","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect evidence via miRNA overexpression, ATL2 not directly manipulated, single lab","pmids":["30879769"],"is_preprint":false},{"year":2024,"finding":"In Drosophila, loss of the atlastin ortholog (atl) from muscle causes autophagy defects and accumulation of polyubiquitin protein aggregates. Increased neuronal excitability enhances this proteomic stress specifically when atl is absent from muscle (not neuron), demonstrating that atlastin in muscle is required for autophagy and protein quality control, and that neuronal activity modulates this requirement.","method":"Drosophila atl2 null mutant, TrpA1 neuronal activation, polyubiquitin aggregate quantification, tissue-specific rescue experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific genetic dissection with defined phenotypic readout, Drosophila ortholog study, single lab","pmids":["38166124"],"is_preprint":false}],"current_model":"ATL2 (atlastin-2) is a membrane-bound dynamin-like GTPase localized to the ER that mediates homotypic ER tubule fusion to generate and maintain the three-way junctions of the polygonal ER tubular network; its GTPase activity is required for normal ER morphology, dendritic Ca2+ signaling (via regulation of RyR2/IP3R distribution), lipid synthesis, and autophagosome initiation site assembly, while Lunapark ubiquitinates ATL2 at specific lysine residues to regulate its activity at three-way junctions, and ATL2 also supports ER-mitochondria contacts (MAMs), flavivirus replication organelle organization via membrane tethering, and non-enveloped virus membrane penetration by maintaining overall ER reticular integrity."},"narrative":{"mechanistic_narrative":"ATL2 (atlastin-2) is a membrane-bound dynamin-like GTPase of the endoplasmic reticulum that drives homotypic fusion of ER tubules to build and maintain the three-way junctions of the polygonal ER network [PMID:18270207, PMID:30773365]. Its function is redundant with the paralogs ATL1 and ATL3 and is conserved across distant orthologs, since re-expression of any single atlastin or the yeast and plant orthologs Sey1p and RHD3 rescues the loss of three-way junctions caused by combined atlastin knockout [PMID:27669642]. This GTPase-dependent fusion activity is required broadly for ER-templated cellular processes: it shapes the dendritic ER that organizes RyR2 and IP3R1 channel distribution and supports normal IP3-evoked Ca2+ signaling [PMID:33812310], sustains lipid (phosphatidylcholine and cholesterol) synthesis and intracellular membrane homeostasis [PMID:bio_10.1101_2025.04.12.648519], and licenses the assembly of FIP200 autophagosome initiation sites on the ER surface [PMID:36198318]. ATL2 activity at three-way junctions is regulated by Lunapark, which ubiquitinates ATL2 at lysines 56, 57, 282, and 302; a ubiquitination-site mutant fails to restore three-way junctions, establishing Lunapark-dependent ubiquitination as a positive determinant of ATL2 network-shaping activity [PMID:35894092], while TMCC3 binds atlastins and acts as a further positive modulator at junctions [PMID:31696206]. ATL2 additionally mediates ER-mitochondria contact formation downstream of mutant presenilin-1 [PMID:34522215] and is co-opted by viruses: it maintains the reticular ER integrity needed for SV40 membrane penetration [PMID:37578227], and its membrane-tethering activity, separable from fusion, organizes the spatial distribution of flavivirus replication organelles [PMID:41394679]. In vivo, ATL2 loss is embryonic lethal with disrupted cerebellar development through disorganized Bergmann glia [PMID:bio_10.1101_2025.04.12.648519].","teleology":[{"year":2008,"claim":"Established that ATL2 is an ER-localized GTPase whose activity is needed to build the reticular ER network, answering whether atlastins shape ER tubules in non-neuronal cells.","evidence":"siRNA knockdown and GTPase-deficient dominant-negative overexpression in HeLa cells with ER/Golgi morphology imaging","pmids":["18270207"],"confidence":"Medium","gaps":["Did not directly demonstrate membrane fusion in vitro","Mechanism of three-way junction formation not resolved at molecular level"]},{"year":2016,"claim":"Resolved whether ATL2 acts redundantly with other atlastins by showing that any single atlastin or a distant ortholog restores ER network formation after triple knockout.","evidence":"CRISPR/Cas9 triple atlastin knockout in NIH-3T3 cells with paralog and ortholog rescue and morphology/differentiation assays","pmids":["27669642"],"confidence":"High","gaps":["Redundancy obscures ATL2-specific contributions","Link between BMP signaling/ER stress and atlastin loss not mechanistically dissected"]},{"year":2019,"claim":"Distinguished ATL2's fusion-driven ER-shaping role from ATL3's ER-phagy receptor function, clarifying functional division of labor among paralogs.","evidence":"siRNA depletion and morphological comparison of ATL2 vs ATL3 in a focused mechanistic study","pmids":["30773365"],"confidence":"Medium","gaps":["Did not test whether ATL2 has any independent non-fusion role"]},{"year":2019,"claim":"Identified TMCC3 as a direct atlastin-binding modulator at three-way junctions, addressing how atlastin activity is positively regulated in the network.","evidence":"Co-IP/binding assays, TMCC3 knockdown, and ATL2 overexpression rescue with ER morphology imaging","pmids":["31696206"],"confidence":"Medium","gaps":["Molecular mechanism by which TMCC3 stimulates atlastin not defined","Direct binding to ATL2 specifically vs other atlastins not isolated"]},{"year":2021,"claim":"Connected ATL2 GTPase activity to dendritic Ca2+ signaling by showing it organizes ER Ca2+ channel distribution in neurons.","evidence":"GTPase-deficient ATL2 mutant expression in hippocampal neurons with live Ca2+ imaging and channel localization","pmids":["33812310"],"confidence":"Medium","gaps":["Whether RyR2/IP3R aggregation is a direct or downstream consequence of ER disruption unresolved","No direct ATL2-channel interaction shown"]},{"year":2021,"claim":"Implicated ATL2 in ER-mitochondria contact formation downstream of an Alzheimer's-linked presenilin-1 mutation.","evidence":"Hippocampal expression profiling, ATL2 siRNA knockdown, and MAM contact quantification","pmids":["34522215"],"confidence":"Medium","gaps":["Direct molecular role of ATL2 at MAMs not defined","Whether effect requires GTPase/fusion activity untested"]},{"year":2021,"claim":"Placed ATL2 in the autophagosome initiation pathway by showing it is required for FIP200 complex assembly on the ER.","evidence":"siRNA depletion, super-resolution imaging of FIP200 puncta, and VAPA/B epistasis","pmids":["36198318"],"confidence":"Medium","gaps":["ATL2-specific contribution separate from ATL3 not isolated","Mechanistic link from ER Ca2+ transients to FIP200 recruitment incomplete"]},{"year":2021,"claim":"Positioned ATL2 within the broader ER-shaping protein network alongside Climp63 in epistasis analysis of NOMO1.","evidence":"Genetic epistasis analysis with siRNA depletion and electron microscopy","pmids":["34224731"],"confidence":"Low","gaps":["ATL2 used as reference rather than directly manipulated","No direct functional interaction with NOMO1 established"]},{"year":2022,"claim":"Defined a regulatory mechanism for ATL2 by identifying Lunapark-mediated ubiquitination at specific lysines as required for three-way junction formation.","evidence":"Co-IP, ubiquitination assays, K-to-R site mutagenesis, and rescue of three-way junctions","pmids":["35894092"],"confidence":"High","gaps":["How ubiquitination biochemically alters ATL2 GTPase/fusion activity unknown","Turnover vs activity-modulation role of the modification unresolved"]},{"year":2023,"claim":"Showed ATL2 supports viral membrane penetration indirectly by maintaining global ER reticular integrity rather than relocalizing to penetration foci.","evidence":"siRNA knockdown, confocal microscopy, and SV40 infectivity assays with ATL3 comparison","pmids":["37578227"],"confidence":"Medium","gaps":["No direct ATL2 interaction with the penetration complex shown","Whether GTPase activity is required not tested"]},{"year":2024,"claim":"Demonstrated, via the Drosophila ortholog, that atlastin in muscle is required for autophagy and protein quality control, and that neuronal activity modulates this requirement.","evidence":"Drosophila atl null mutant, tissue-specific rescue, TrpA1 neuronal activation, and polyubiquitin aggregate quantification","pmids":["38166124"],"confidence":"Medium","gaps":["Ortholog study may not map directly to mammalian ATL2","Molecular basis of activity-dependent proteostatic stress unknown"]},{"year":2025,"claim":"Separated ATL2's membrane-tethering activity from its fusion activity, showing tethering alone is sufficient to organize flavivirus replication organelles.","evidence":"ATL2 knockout with tethering-competent/fusion-defective mutant rescue, EM, and viral replication assays (preprint)","pmids":["41394679"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","How tethering spatially organizes vROs mechanistically unclear"]},{"year":2025,"claim":"Established the in vivo requirement for ATL2 in development and lipid homeostasis, showing knockout is embryonic lethal with cerebellar defects and reduced lipid synthesis.","evidence":"ATL2 knockout mice, cerebellar histology, glia positioning analysis, and lipidomics (preprint)","pmids":["bio_10.1101_2025.04.12.648519"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Causal chain from ER fusion to lipid synthesis decline not mechanistically resolved","Cell-autonomous vs non-autonomous basis of cerebellar phenotype unclear"]},{"year":null,"claim":"How ATL2's distinct activities — tethering versus fusion — are differentially deployed across its many roles (Ca2+ signaling, autophagy initiation, MAMs, lipid synthesis, viral organelle organization) and how ubiquitination integrates these remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking GTPase cycle to tethering vs fusion outcomes","Mechanistic coupling between ER shaping and downstream lipid/Ca2+/autophagy functions undefined","No reported human Mendelian disease link in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,1,3,10]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,2,4]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10]}],"complexes":[],"partners":["LNP1","TMCC3","ATL3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NHH9","full_name":"Atlastin-2","aliases":["ADP-ribosylation factor-like protein 6-interacting protein 2"],"length_aa":583,"mass_kda":66.2,"function":"Atlastin-2 (ATL2) 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:22065636, PubMed:27619977, PubMed:34817557). Two atlastin-2 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/Q8NHH9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ATL2","classification":"Common Essential","n_dependent_lines":866,"n_total_lines":1208,"dependency_fraction":0.7168874172185431},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000119787","cell_line_id":"CID000366","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"ATL3","stoichiometry":4.0},{"gene":"COPB2","stoichiometry":4.0},{"gene":"COPG2","stoichiometry":4.0},{"gene":"ARL6IP1","stoichiometry":0.2},{"gene":"ESYT1","stoichiometry":0.2},{"gene":"IDH1","stoichiometry":0.2},{"gene":"COPA","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"COPG1","stoichiometry":0.2},{"gene":"COPZ1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000366","total_profiled":1310},"omim":[{"mim_id":"610243","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 27; ZFYVE27","url":"https://www.omim.org/entry/610243"},{"mim_id":"609368","title":"ATLASTIN GTPase 2; ATL2","url":"https://www.omim.org/entry/609368"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATL2"},"hgnc":{"alias_symbol":["atlastin2"],"prev_symbol":["ARL6IP2"]},"alphafold":{"accession":"Q8NHH9","domains":[{"cath_id":"3.40.50.300","chopping":"61-365","consensus_level":"high","plddt":91.695,"start":61,"end":365},{"cath_id":"1.20.58.420","chopping":"377-466","consensus_level":"high","plddt":92.162,"start":377,"end":466},{"cath_id":"-","chopping":"469-577","consensus_level":"high","plddt":81.266,"start":469,"end":577}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHH9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHH9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHH9-F1-predicted_aligned_error_v6.png","plddt_mean":84.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATL2","jax_strain_url":"https://www.jax.org/strain/search?query=ATL2"},"sequence":{"accession":"Q8NHH9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NHH9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NHH9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHH9"}},"corpus_meta":[{"pmid":"2578514","id":"PMC_2578514","title":"TCGF (IL 2)-receptor inducing factor(s). 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Knockdown of ATL2 in HeLa cells by siRNA disrupts Golgi morphology, and expression of dominant-negative (GTPase-deficient) atlastin proteins causes prominent inhibition of ER reticularization, specifically blocking formation of three-way junctions in the ER tubular network.\",\n      \"method\": \"siRNA knockdown in HeLa cells, dominant-negative overexpression, fluorescence microscopy of ER and Golgi morphology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean siRNA KD plus dominant-negative OE with defined morphological phenotype, single lab, two complementary approaches\",\n      \"pmids\": [\"18270207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Triple CRISPR/Cas9 knockout of all three atlastins (Atl1/2/3) in NIH-3T3 cells causes marked disruption of ER morphology with prominent impairment of three-way ER tubule junction formation. This phenotype is rescued by re-expression of any single human atlastin (ATL1, ATL2, or ATL3), or distant orthologs from yeast (Sey1p) or Arabidopsis (RHD3), establishing ATL2 as functionally redundant with paralogs in ER network formation. Atlastins are also required for proper adipocyte-like differentiation of NIH-3T3 cells, and their loss alters BMP signaling and increases ER stress sensitivity.\",\n      \"method\": \"CRISPR/Cas9 triple knockout, rescue expression assays, fluorescence microscopy of ER morphology, differentiation assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with multiple orthogonal rescue experiments (three paralogs + two distant orthologs), defined cellular phenotype, rigorous controls\",\n      \"pmids\": [\"27669642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATL2 predominantly affects ER morphology by promoting ER tubule fusion (consistent with its GTPase activity), whereas ATL3 has a distinct role as an ER-phagy receptor. ATL2 depletion causes detectable alterations in ER morphology, distinguishing it functionally from ATL3 depletion which barely alters ER morphology.\",\n      \"method\": \"siRNA depletion, fluorescence microscopy of ER morphology, functional comparison with ATL3\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cited as established prior work within a focused mechanistic study; single lab, morphological readout\",\n      \"pmids\": [\"30773365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATL2 GTPase activity is required for normal IP3-induced dendritic Ca2+ signaling in hippocampal neurons. GTPase-deficient ATL2 mutants cause ER morphological alterations, delay the onset and increase the rising time of IP3-evoked Ca2+ signals, and cause RyR2 and IP3R1 channel aggregation and RyR2 redistribution in dendrites.\",\n      \"method\": \"Expression of GTPase-deficient ATL2 mutants in primary hippocampal neurons, live Ca2+ imaging, fluorescence microscopy of ER morphology and Ca2+ channel distribution\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — active-site mutagenesis combined with functional Ca2+ imaging and localization, single lab\",\n      \"pmids\": [\"33812310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lunapark (Lnp) ubiquitinates ATL2 at lysines 56, 57, 282, and 302. Lnp localization to ER three-way junctions is required for ATL2 ubiquitination. Expression of an ATL2 ubiquitination-site mutant (K→R substitutions) fails to rescue the decrease in three-way junctions caused by ATL2 knockdown, indicating that Lnp-mediated ubiquitination of ATL2 is required for proper tubular ER network formation.\",\n      \"method\": \"Co-IP, ubiquitination assays, site-directed mutagenesis, siRNA knockdown, rescue expression, fluorescence microscopy of ER three-way junctions\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical ubiquitination assay with mutagenesis identifying specific sites, functional rescue experiment, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35894092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TMCC3 physically binds to atlastins (including ATL2) through its C-terminal transmembrane domains and localizes to ER three-way junctions. TMCC3 knockdown decreases three-way junctions and expands ER sheets; this phenotype is partially rescued by ATL2 overexpression, placing TMCC3 as a positive modulator of atlastin activity at three-way junctions.\",\n      \"method\": \"Co-IP/binding assays, siRNA knockdown, ATL2 overexpression rescue, fluorescence microscopy of ER morphology\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding assay plus epistatic rescue, single lab, two orthogonal approaches\",\n      \"pmids\": [\"31696206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATL2 expression is upregulated by the Alzheimer's disease-linked PS1 M146V mutation and contributes to elevated ER-mitochondria contacts (MAMs). Downregulation of ATL2 after PS1 mutant induction rescued the abnormally elevated ER-mitochondria interactions back to normal levels, identifying ATL2 as a mediator of ER-mitochondria contact sites downstream of mutant presenilin-1.\",\n      \"method\": \"Comparative hippocampal gene expression profiling, ATL2 siRNA knockdown, ER-mitochondria contact site quantification, Western blotting\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined phenotypic readout (MAM contacts), single lab, supported by in vivo brain expression data\",\n      \"pmids\": [\"34522215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATL2 and ATL3 are required for the association of multiple FIP200 autophagosome initiation complexes on the ER surface. Depletion of ATL2/3 impairs the assembly of FIP200 puncta into autophagosome formation sites, placing ATL2 in the pathway linking ER Ca2+ transients to autophagosome initiation.\",\n      \"method\": \"siRNA depletion, multi-modal SIM analysis, live imaging of FIP200 puncta, epistasis with VAPA/B\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined autophagy initiation phenotype in a high-rigor study, single paper for ATL2-specific role\",\n      \"pmids\": [\"36198318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ATL2 supports the reticular ER morphology required for the integrity of the ATL3-dependent membrane penetration complex during SV40 (polyomavirus) infection. Unlike ATL3, ATL2 does not reorganize to ER-foci (membrane penetration sites); instead it maintains the overall ER tubular network that is critical for the ATL3-containing complex. ATL2 knockdown impairs SV40 infection.\",\n      \"method\": \"siRNA knockdown, confocal microscopy, viral infectivity assays, mechanistic comparison with ATL3\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined infectivity phenotype and localization distinction from ATL3, single lab\",\n      \"pmids\": [\"37578227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATL2 depletion reduces the spatial distribution of flavivirus (DENV, ZIKV) viral replication organelles (vROs) within infected cells, decreases virus production, and induces innate immune responses. A tethering-competent but fusion-defective ATL2 mutant is sufficient to rescue DENV and ZIKV replication in ATL2-knockout cells, demonstrating that ATL2's membrane-tethering activity (not its fusion activity) is required for vRO organization.\",\n      \"method\": \"ATL2 knockout, ATL2 tethering/fusion mutant rescue, confocal and electron microscopy, viral replication assays, innate immune response measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis separating tethering from fusion activity with functional rescue, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41394679\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ATL2 knockout mice are embryonic lethal with compromised cerebellar development. ATL2 is highly expressed in neuroglia and its loss disorganizes Bergmann glia positioning, interfering with granule cell migration. ATL2-null cells show reduced intracellular membrane area associated with decreased phosphatidylcholine and cholesterol synthesis, indicating ATL2's GTPase-mediated ER fusion activity is required for sustained lipid synthesis and membrane homeostasis.\",\n      \"method\": \"ATL2 knockout mice, cerebellar histology, glia positioning analysis, lipidomics, membrane area quantification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with defined developmental phenotype and lipidomics, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.04.12.648519\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A genetic epistasis analysis placing ATL2 within the network of ER-shaping proteins: NOMO1 depletion causes ER morphology collapse, and this was analyzed in the context of known ER-shaping proteins including Atlastin2 and Climp63, establishing ATL2 as part of the functional network maintaining ER structural integrity.\",\n      \"method\": \"Genetic epistasis analysis, siRNA depletion, electron microscopy of ER morphology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ATL2 used as epistasis reference rather than direct subject of experiment; single paper, indirect evidence\",\n      \"pmids\": [\"34224731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-30b-5p overexpression in mouse mammary epithelial cells causes downregulation of ATL2 expression, leading to fragmented ER tubular network and increased lipid droplet size, suggesting ATL2 plays a role in lipid droplet formation and ER morphology maintenance in mammary epithelial cells.\",\n      \"method\": \"Transgenic mouse model with miR-30b-5p overexpression, electron microscopy of ER, lipid droplet quantification, miRNA target validation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect evidence via miRNA overexpression, ATL2 not directly manipulated, single lab\",\n      \"pmids\": [\"30879769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Drosophila, loss of the atlastin ortholog (atl) from muscle causes autophagy defects and accumulation of polyubiquitin protein aggregates. Increased neuronal excitability enhances this proteomic stress specifically when atl is absent from muscle (not neuron), demonstrating that atlastin in muscle is required for autophagy and protein quality control, and that neuronal activity modulates this requirement.\",\n      \"method\": \"Drosophila atl2 null mutant, TrpA1 neuronal activation, polyubiquitin aggregate quantification, tissue-specific rescue experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific genetic dissection with defined phenotypic readout, Drosophila ortholog study, single lab\",\n      \"pmids\": [\"38166124\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATL2 (atlastin-2) is a membrane-bound dynamin-like GTPase localized to the ER that mediates homotypic ER tubule fusion to generate and maintain the three-way junctions of the polygonal ER tubular network; its GTPase activity is required for normal ER morphology, dendritic Ca2+ signaling (via regulation of RyR2/IP3R distribution), lipid synthesis, and autophagosome initiation site assembly, while Lunapark ubiquitinates ATL2 at specific lysine residues to regulate its activity at three-way junctions, and ATL2 also supports ER-mitochondria contacts (MAMs), flavivirus replication organelle organization via membrane tethering, and non-enveloped virus membrane penetration by maintaining overall ER reticular integrity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATL2 (atlastin-2) is a membrane-bound dynamin-like GTPase of the endoplasmic reticulum that drives homotypic fusion of ER tubules to build and maintain the three-way junctions of the polygonal ER network [#0, #2]. Its function is redundant with the paralogs ATL1 and ATL3 and is conserved across distant orthologs, since re-expression of any single atlastin or the yeast and plant orthologs Sey1p and RHD3 rescues the loss of three-way junctions caused by combined atlastin knockout [#1]. This GTPase-dependent fusion activity is required broadly for ER-templated cellular processes: it shapes the dendritic ER that organizes RyR2 and IP3R1 channel distribution and supports normal IP3-evoked Ca2+ signaling [#3], sustains lipid (phosphatidylcholine and cholesterol) synthesis and intracellular membrane homeostasis [#10], and licenses the assembly of FIP200 autophagosome initiation sites on the ER surface [#7]. ATL2 activity at three-way junctions is regulated by Lunapark, which ubiquitinates ATL2 at lysines 56, 57, 282, and 302; a ubiquitination-site mutant fails to restore three-way junctions, establishing Lunapark-dependent ubiquitination as a positive determinant of ATL2 network-shaping activity [#4], while TMCC3 binds atlastins and acts as a further positive modulator at junctions [#5]. ATL2 additionally mediates ER-mitochondria contact formation downstream of mutant presenilin-1 [#6] and is co-opted by viruses: it maintains the reticular ER integrity needed for SV40 membrane penetration [#8], and its membrane-tethering activity, separable from fusion, organizes the spatial distribution of flavivirus replication organelles [#9]. In vivo, ATL2 loss is embryonic lethal with disrupted cerebellar development through disorganized Bergmann glia [#10].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that ATL2 is an ER-localized GTPase whose activity is needed to build the reticular ER network, answering whether atlastins shape ER tubules in non-neuronal cells.\",\n      \"evidence\": \"siRNA knockdown and GTPase-deficient dominant-negative overexpression in HeLa cells with ER/Golgi morphology imaging\",\n      \"pmids\": [\"18270207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not directly demonstrate membrane fusion in vitro\", \"Mechanism of three-way junction formation not resolved at molecular level\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved whether ATL2 acts redundantly with other atlastins by showing that any single atlastin or a distant ortholog restores ER network formation after triple knockout.\",\n      \"evidence\": \"CRISPR/Cas9 triple atlastin knockout in NIH-3T3 cells with paralog and ortholog rescue and morphology/differentiation assays\",\n      \"pmids\": [\"27669642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy obscures ATL2-specific contributions\", \"Link between BMP signaling/ER stress and atlastin loss not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Distinguished ATL2's fusion-driven ER-shaping role from ATL3's ER-phagy receptor function, clarifying functional division of labor among paralogs.\",\n      \"evidence\": \"siRNA depletion and morphological comparison of ATL2 vs ATL3 in a focused mechanistic study\",\n      \"pmids\": [\"30773365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not test whether ATL2 has any independent non-fusion role\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified TMCC3 as a direct atlastin-binding modulator at three-way junctions, addressing how atlastin activity is positively regulated in the network.\",\n      \"evidence\": \"Co-IP/binding assays, TMCC3 knockdown, and ATL2 overexpression rescue with ER morphology imaging\",\n      \"pmids\": [\"31696206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which TMCC3 stimulates atlastin not defined\", \"Direct binding to ATL2 specifically vs other atlastins not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected ATL2 GTPase activity to dendritic Ca2+ signaling by showing it organizes ER Ca2+ channel distribution in neurons.\",\n      \"evidence\": \"GTPase-deficient ATL2 mutant expression in hippocampal neurons with live Ca2+ imaging and channel localization\",\n      \"pmids\": [\"33812310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RyR2/IP3R aggregation is a direct or downstream consequence of ER disruption unresolved\", \"No direct ATL2-channel interaction shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated ATL2 in ER-mitochondria contact formation downstream of an Alzheimer's-linked presenilin-1 mutation.\",\n      \"evidence\": \"Hippocampal expression profiling, ATL2 siRNA knockdown, and MAM contact quantification\",\n      \"pmids\": [\"34522215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular role of ATL2 at MAMs not defined\", \"Whether effect requires GTPase/fusion activity untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed ATL2 in the autophagosome initiation pathway by showing it is required for FIP200 complex assembly on the ER.\",\n      \"evidence\": \"siRNA depletion, super-resolution imaging of FIP200 puncta, and VAPA/B epistasis\",\n      \"pmids\": [\"36198318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ATL2-specific contribution separate from ATL3 not isolated\", \"Mechanistic link from ER Ca2+ transients to FIP200 recruitment incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioned ATL2 within the broader ER-shaping protein network alongside Climp63 in epistasis analysis of NOMO1.\",\n      \"evidence\": \"Genetic epistasis analysis with siRNA depletion and electron microscopy\",\n      \"pmids\": [\"34224731\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"ATL2 used as reference rather than directly manipulated\", \"No direct functional interaction with NOMO1 established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a regulatory mechanism for ATL2 by identifying Lunapark-mediated ubiquitination at specific lysines as required for three-way junction formation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, K-to-R site mutagenesis, and rescue of three-way junctions\",\n      \"pmids\": [\"35894092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ubiquitination biochemically alters ATL2 GTPase/fusion activity unknown\", \"Turnover vs activity-modulation role of the modification unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed ATL2 supports viral membrane penetration indirectly by maintaining global ER reticular integrity rather than relocalizing to penetration foci.\",\n      \"evidence\": \"siRNA knockdown, confocal microscopy, and SV40 infectivity assays with ATL3 comparison\",\n      \"pmids\": [\"37578227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct ATL2 interaction with the penetration complex shown\", \"Whether GTPase activity is required not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated, via the Drosophila ortholog, that atlastin in muscle is required for autophagy and protein quality control, and that neuronal activity modulates this requirement.\",\n      \"evidence\": \"Drosophila atl null mutant, tissue-specific rescue, TrpA1 neuronal activation, and polyubiquitin aggregate quantification\",\n      \"pmids\": [\"38166124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog study may not map directly to mammalian ATL2\", \"Molecular basis of activity-dependent proteostatic stress unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Separated ATL2's membrane-tethering activity from its fusion activity, showing tethering alone is sufficient to organize flavivirus replication organelles.\",\n      \"evidence\": \"ATL2 knockout with tethering-competent/fusion-defective mutant rescue, EM, and viral replication assays (preprint)\",\n      \"pmids\": [\"41394679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"How tethering spatially organizes vROs mechanistically unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established the in vivo requirement for ATL2 in development and lipid homeostasis, showing knockout is embryonic lethal with cerebellar defects and reduced lipid synthesis.\",\n      \"evidence\": \"ATL2 knockout mice, cerebellar histology, glia positioning analysis, and lipidomics (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.12.648519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Causal chain from ER fusion to lipid synthesis decline not mechanistically resolved\", \"Cell-autonomous vs non-autonomous basis of cerebellar phenotype unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATL2's distinct activities — tethering versus fusion — are differentially deployed across its many roles (Ca2+ signaling, autophagy initiation, MAMs, lipid synthesis, viral organelle organization) and how ubiquitination integrates these remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking GTPase cycle to tethering vs fusion outcomes\", \"Mechanistic coupling between ER shaping and downstream lipid/Ca2+/autophagy functions undefined\", \"No reported human Mendelian disease link in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1, 3, 10]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"GO:0005789\", \"supporting_discovery_ids\": []}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LNP1\",\n      \"TMCC3\",\n      \"ATL3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}