{"gene":"ACBD5","run_date":"2026-06-09T22:02:38","timeline":{"discoveries":[{"year":2017,"finding":"ACBD5 (peroxisomal membrane protein) directly interacts with ER-resident VAPA and VAPB to tether peroxisomes to the ER; depletion of either ACBD5 or VAP increases peroxisome mobility, indicating the VAP-ACBD5 complex acts as the primary ER-peroxisome tether. This tethering is required for peroxisome growth, plasmalogen phospholipid synthesis, and maintenance of cellular cholesterol levels.","method":"Co-immunoprecipitation, knockdown/depletion, live-cell imaging of peroxisome mobility, lipid biochemistry","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and functional depletion with defined organellar and lipid phenotypes; independently replicated in two concurrent papers (PMID:28108526 and PMID:28108524)","pmids":["28108526","28108524"],"is_preprint":false},{"year":2017,"finding":"ACBD5 binds to VAPB via an FFAT-like motif interacting with VAPB's major sperm protein (MSP) domain; loss of ACBD5-VAPB interaction reduces peroxisome-ER associations and increases peroxisome movement, and also perturbs peroxisome membrane expansion.","method":"Co-immunoprecipitation, FFAT-motif mapping, live-cell imaging, electron microscopy of contact sites","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-level binding characterization with reciprocal Co-IP, functional ER-contact and mobility assays, replicated across two independent labs","pmids":["28108524","28108526"],"is_preprint":false},{"year":2016,"finding":"ACBD5 deficiency (patient mutation and CRISPR-Cas9 KO in HeLa cells) causes accumulation of very long-chain fatty acids (VLCFAs) due to impaired peroxisomal β-oxidation; the proposed mechanism is that ACBD5 sequesters C26-CoA in the cytosol to facilitate transport into peroxisomes. No effect on pexophagy was detected.","method":"CRISPR-Cas9 knockout, patient-derived fibroblasts, biochemical VLCFA measurement, pexophagy assay","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — independently replicated by two concurrent papers using patient material and genome-edited cell lines with defined biochemical readouts","pmids":["27799409","27899449"],"is_preprint":false},{"year":2016,"finding":"ACBD5 is a peroxisomal tail-anchored membrane protein that exposes its acyl-CoA binding domain (ACBD) to the cytosol; it preferentially binds very-long-chain fatty acyl-CoAs (VLC-CoAs). Both the N-terminal ACBD and peroxisomal localization are required for efficient VLCFA β-oxidation. ACBD5 deficiency elevates cellular phospholipids containing VLCFAs without affecting peroxisome biogenesis or import of membrane/matrix proteins.","method":"Subcellular fractionation, domain mutagenesis, in vitro acyl-CoA binding assay, KO cell lines (patient fibroblasts and CRISPR HeLa), lipidomics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding assay plus domain mutagenesis plus KO phenotype in a single rigorous study","pmids":["27899449"],"is_preprint":false},{"year":2022,"finding":"Peroxisome-ER contacts via the ACBD5-VAPB tether are regulated by phosphorylation: GSK3β phosphorylates sites in the flanking regions and core of the ACBD5 FFAT-like motif, altering VAPB binding and thus peroxisome-ER contact site formation. The interaction is phosphatase-sensitive.","method":"Phosphorylation site mapping (mass spectrometry), phospho-mimetic/phospho-dead mutagenesis, GSK3β inhibitor treatment, proximity ligation assay for contact sites, Co-IP","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phosphorylation site identified by MS, functionally validated by mutagenesis and kinase inhibition with defined contact-site phenotype","pmids":["35019937"],"is_preprint":false},{"year":2018,"finding":"Overexpression of ACBD5 in hippocampal neurons reduces peroxisomal long-range movements in neurites by ~70% and redistributes peroxisomes toward the cell periphery and into neurites; this effect is independent of VAPB binding, as an ACBD5 variant unable to bind VAPB produces the same redistribution, suggesting additional ACBD5-binding partners tether peroxisomes near the plasma membrane in neurons.","method":"Confocal live-cell imaging in cultured hippocampal neurons, transfection with ACBD5 wild-type and VAPB-binding-deficient mutant, quantification of peroxisome motility and distribution","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct live imaging with VAPB-binding mutant used to dissect mechanism, single lab, single cell-type system","pmids":["30589881"],"is_preprint":false},{"year":2023,"finding":"ACBD5 and ACBD4 interact with each other independently of VAPB binding. ACBD5 acts as the primary peroxisome-ER tether and VLCFA recruitment factor, whereas ACBD4 has regulatory functions: loss of ACBD4 increases the rate of VLCFA β-oxidation rather than decreasing it, and does not reduce peroxisome-ER contacts or cause VLCFA accumulation.","method":"Co-immunoprecipitation (ACBD4-ACBD5 interaction), KO of ACBD4 or ACBD5 in HEK293 cells, lipidomics, peroxisome-ER contact site quantification","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for interaction plus KO phenotype with lipidomics, single lab with multiple orthogonal methods","pmids":["37414147"],"is_preprint":false},{"year":2014,"finding":"In a radiation-induced papillary thyroid cancer, ACBD5 is fused to RET by pericentric inversion inv(10)(p12.1;q11.2); the resulting ACBD5-RET fusion protein activates ERK/MAPK signaling (enhanced ERK phosphorylation) and induces tumor formation in nude mouse xenografts, indicating oncogenic activity of this rearrangement.","method":"5' RACE, RT-PCR, transfection of full-length ACBD5-RET cDNA into NIH3T3 cells, Western blot for ERK phosphorylation, xenograft tumor formation assay","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional in vitro and in vivo assays for the fusion protein, but single lab and single case; finding is about a fusion gene, not native ACBD5 function","pmids":["25175022"],"is_preprint":false},{"year":2024,"finding":"In Acbd5-deficient mice (CRISPR Gly357* allele), VLCFA accumulation leads to deregulated cytoskeleton with reduced actin dynamics and increased neuronal filopodia (shown in neurons treated with VLCFA); AAV-mediated gene delivery of ACBD5 ameliorated gait phenotypes, giant axonopathy, myelination defects, and astrocyte reactivity.","method":"CRISPR/Cas9 mouse model, lipidomics, proteomics, functional actin dynamics assay in VLCFA-treated neurons, AAV gene therapy rescue experiment","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with rescue experiment and mechanistic follow-up in neurons, single lab","pmids":["38066620"],"is_preprint":false},{"year":2025,"finding":"In ACBD5-deficient mouse retina, VLC-PUFAs specifically accumulate in phosphatidylcholines of the inner retinal plexiform layers (OPL to IPL) rather than in photoreceptor outer segments; photoreceptor ribbon synapses at the OPL show ultrastructural degeneration, and ffERG reveals severe functional dysregulation of retinal signal transduction, pointing to cell-type-specific disruption of lipid homeostasis as the pathogenic mechanism.","method":"Immunofluorescence microscopy, electron microscopy, full-field electroretinography, MALDI MS imaging-based spatial lipidomics","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal methods in a mouse model, but single lab and mechanistic interpretation is correlative","pmids":["41324649"],"is_preprint":false},{"year":2024,"finding":"Phylogenetic and experimental analyses show that ACBD5's peroxisome-ER tethering function via the FFAT motif is conserved in vertebrates and in Drosophila (where the single ACBD4/5-like protein uses its FFAT motif to tether peroxisomes to the ER via Dm_Vap33); the filamentous fungus Ustilago maydis ACBD4/5-like protein lacks a FFAT motif and does not interact with Um_Vap33, indicating the tethering function was acquired during animal evolution.","method":"Phylogenetic analysis, FFAT motif mutagenesis, Co-IP (Drosophila and fungal proteins with VAP orthologs), RNAi depletion of Dm_Acbd4/5 with peroxisome distribution readout","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, Co-IP and RNAi in non-mammalian organisms; mechanistic conclusions about human ACBD5 are indirect","pmids":[],"is_preprint":true}],"current_model":"ACBD5 is a peroxisomal tail-anchored membrane protein that exposes its acyl-CoA binding domain to the cytosol, where it captures very-long-chain fatty acyl-CoAs (VLC-CoAs) to facilitate their import into peroxisomes for β-oxidation; it simultaneously tethers peroxisomes to the ER by binding ER-resident VAPA/VAPB through an FFAT-like motif—an interaction regulated by GSK3β-mediated phosphorylation—thereby enabling lipid exchange, plasmalogen synthesis, cholesterol homeostasis, and peroxisome membrane expansion, while also interacting with paralog ACBD4 at the peroxisome-ER interface in a regulatory capacity."},"narrative":{"mechanistic_narrative":"ACBD5 is a peroxisomal tail-anchored membrane protein that couples very-long-chain fatty acid (VLCFA) metabolism to inter-organelle membrane contact, exposing an N-terminal acyl-CoA binding domain (ACBD) to the cytosol where it preferentially captures very-long-chain fatty acyl-CoAs and channels them into peroxisomes for β-oxidation; loss of ACBD5 or its ACBD causes cellular accumulation of VLCFAs and VLCFA-containing phospholipids without disrupting peroxisome biogenesis or protein import [PMID:27799409, PMID:27899449]. Independently of this metabolic role, ACBD5 serves as the primary ER–peroxisome tether: through an FFAT-like motif it binds the MSP domain of the ER-resident proteins VAPA and VAPB, and loss of this interaction reduces peroxisome–ER contacts, increases peroxisome mobility, and impairs peroxisome growth, plasmalogen synthesis, and cholesterol homeostasis [PMID:28108526, PMID:28108524]. Tether formation is dynamically controlled by GSK3β phosphorylation of the FFAT-like motif and its flanking regions, which modulates VAPB binding in a phosphatase-sensitive manner [PMID:35019937]. ACBD5 also interacts with its paralog ACBD4 in a VAPB-independent fashion, with ACBD4 exerting a regulatory rather than tethering role over VLCFA β-oxidation [PMID:37414147]. Functionally, ACBD5 deficiency drives neurological and retinal pathology: in mouse models, VLCFA accumulation deregulates actin dynamics and produces axonopathy, myelination defects, and cell-type-specific retinal lipid accumulation with synaptic degeneration, and AAV-mediated ACBD5 delivery ameliorates the neurological phenotypes [PMID:38066620, PMID:41324649]. A radiation-induced ACBD5-RET gene fusion activates ERK/MAPK signaling and is oncogenic, but this reflects the fusion product rather than native ACBD5 function [PMID:25175022].","teleology":[{"year":2014,"claim":"Before native ACBD5 function was defined, a chromosomal rearrangement revealed the locus could contribute an oncogenic fusion, establishing ACBD5 as a fusion partner driving aberrant signaling.","evidence":"5' RACE/RT-PCR identification of an ACBD5-RET fusion, transfection into NIH3T3, ERK phosphorylation Western blot, and xenograft tumor formation","pmids":["25175022"],"confidence":"Medium","gaps":["Concerns the ACBD5-RET fusion protein, not native ACBD5 biology","Single case and single lab","Does not address normal cellular function of ACBD5"]},{"year":2016,"claim":"It was unknown how ACBD5 contributes to lipid metabolism; demonstrating that it is a peroxisomal tail-anchored protein with a cytosol-facing ACBD that binds VLC-CoAs and is required for VLCFA β-oxidation established ACBD5 as a substrate-recruitment factor for peroxisomal fatty acid degradation.","evidence":"Subcellular fractionation, domain mutagenesis, in vitro acyl-CoA binding, CRISPR and patient-derived KO cells, lipidomics, and VLCFA biochemistry","pmids":["27799409","27899449"],"confidence":"High","gaps":["Mechanism of how captured VLC-CoAs cross the peroxisomal membrane not resolved","Whether ACBD5 hands off substrate to a specific transporter unknown","No structural model of the ACBD–acyl-CoA interaction"]},{"year":2017,"claim":"The molecular basis of ER–peroxisome contacts was unclear; identifying ACBD5 as the FFAT-motif partner of ER VAPA/VAPB established the ACBD5–VAP complex as the primary ER–peroxisome tether required for peroxisome growth and lipid homeostasis.","evidence":"Reciprocal Co-IP, FFAT-motif mapping, knockdown, live-cell peroxisome mobility imaging, electron microscopy of contact sites, and lipid biochemistry, replicated across two concurrent papers","pmids":["28108526","28108524"],"confidence":"High","gaps":["How tethering mechanistically enables plasmalogen and cholesterol homeostasis not fully resolved","Whether lipid transfer occurs directly at the contact not shown","Relationship between the tethering and VLC-CoA capture functions not integrated"]},{"year":2018,"claim":"Whether ACBD5 tethering relied solely on VAPB was untested; showing that ACBD5 overexpression redistributes neuronal peroxisomes independently of VAPB binding implied additional, undefined ACBD5 partners anchor peroxisomes in neurons.","evidence":"Confocal live-cell imaging in hippocampal neurons with wild-type and VAPB-binding-deficient ACBD5, quantifying peroxisome motility and distribution","pmids":["30589881"],"confidence":"Medium","gaps":["The proposed additional peripheral tethering partners are not identified","Single cell-type, overexpression-based system","Physiological relevance of the redistribution not established"]},{"year":2022,"claim":"How ER–peroxisome contacts are regulated was unknown; identifying GSK3β phosphorylation of the ACBD5 FFAT-like motif as a switch for VAPB binding established a signaling mechanism controlling contact-site dynamics.","evidence":"Mass spectrometry phospho-site mapping, phospho-mimetic/dead mutagenesis, GSK3β inhibition, proximity ligation assay, and Co-IP","pmids":["35019937"],"confidence":"High","gaps":["Upstream signals activating GSK3β toward ACBD5 unknown","Whether phosphorylation also affects VLC-CoA capture not tested","Counteracting phosphatase not identified"]},{"year":2023,"claim":"The role of the ACBD5 paralog ACBD4 was unclear; showing ACBD4 binds ACBD5 independently of VAPB and that its loss increases rather than decreases VLCFA β-oxidation established ACBD4 as a regulatory rather than tethering factor.","evidence":"Co-IP for ACBD4-ACBD5 interaction, KO of each gene in HEK293, lipidomics, and contact-site quantification","pmids":["37414147"],"confidence":"Medium","gaps":["Mechanism by which ACBD4 restrains β-oxidation not defined","Stoichiometry of an ACBD4-ACBD5 complex unknown","Single-lab study"]},{"year":2024,"claim":"The link between ACBD5 loss and neuropathology was undefined in vivo; an Acbd5-deficient mouse showed VLCFA-driven cytoskeletal deregulation, axonopathy, and myelination defects rescuable by AAV-delivered ACBD5, establishing causal disease mechanism and therapeutic proof-of-concept.","evidence":"CRISPR Gly357* mouse, lipidomics, proteomics, actin dynamics assay in VLCFA-treated neurons, and AAV gene-therapy rescue","pmids":["38066620"],"confidence":"Medium","gaps":["Direct molecular link between VLCFA accumulation and actin deregulation not fully mechanistic","Single lab","Long-term durability of AAV rescue not addressed"]},{"year":2025,"claim":"Why ACBD5 loss causes retinal disease was unclear; spatial lipidomics revealing cell-type-specific VLC-PUFA accumulation in inner retinal layers with ribbon-synapse degeneration established a localized lipid-homeostasis defect as the retinal pathogenic mechanism.","evidence":"Immunofluorescence, electron microscopy, full-field electroretinography, and MALDI MS imaging spatial lipidomics in ACBD5-deficient mouse retina","pmids":["41324649"],"confidence":"Medium","gaps":["Causal link between lipid accumulation and synaptic degeneration is correlative","Why specific retinal layers are affected unexplained","Single lab"]},{"year":null,"claim":"How ACBD5's VLC-CoA capture and ER tethering functions are mechanistically integrated, and the identity of the non-VAP partners that anchor peroxisomes in neurons, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of ACBD5 or its complexes","Mechanism of VLC-CoA membrane translocation downstream of capture unknown","Additional neuronal tethering partners unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["VAPA","VAPB","ACBD4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T8D3","full_name":"Acyl-CoA-binding domain-containing protein 5","aliases":[],"length_aa":534,"mass_kda":60.1,"function":"Acyl-CoA binding protein which acts as the peroxisome receptor for pexophagy but is dispensable for aggrephagy and nonselective autophagy. Binds medium- and long-chain acyl-CoA esters","subcellular_location":"Peroxisome membrane","url":"https://www.uniprot.org/uniprotkb/Q5T8D3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACBD5","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ACBD5","total_profiled":1310},"omim":[{"mim_id":"618863","title":"RETINAL DYSTROPHY WITH LEUKODYSTROPHY; RDLKD","url":"https://www.omim.org/entry/618863"},{"mim_id":"616618","title":"ACYL-CoA-BINDING DOMAIN-CONTAINING PROTEIN 5; ACBD5","url":"https://www.omim.org/entry/616618"},{"mim_id":"611873","title":"REGULATOR OF MICROTUBULE DYNAMICS 3; RMDN3","url":"https://www.omim.org/entry/611873"},{"mim_id":"610855","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 26; ANKRD26","url":"https://www.omim.org/entry/610855"},{"mim_id":"188000","title":"THROMBOCYTOPENIA 2; THC2","url":"https://www.omim.org/entry/188000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Peroxisomes","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACBD5"},"hgnc":{"alias_symbol":["DKFZp434A2417","KIAA1996"],"prev_symbol":[]},"alphafold":{"accession":"Q5T8D3","domains":[{"cath_id":"1.20.80.10","chopping":"26-128","consensus_level":"high","plddt":84.7358,"start":26,"end":128}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T8D3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T8D3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T8D3-F1-predicted_aligned_error_v6.png","plddt_mean":56.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACBD5","jax_strain_url":"https://www.jax.org/strain/search?query=ACBD5"},"sequence":{"accession":"Q5T8D3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T8D3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T8D3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T8D3"}},"corpus_meta":[{"pmid":"28108526","id":"PMC_28108526","title":"VAPs and ACBD5 tether peroxisomes to the ER for peroxisome maintenance and lipid homeostasis.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28108526","citation_count":226,"is_preprint":false},{"pmid":"28108524","id":"PMC_28108524","title":"ACBD5 and VAPB mediate membrane associations between peroxisomes and the ER.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28108524","citation_count":212,"is_preprint":false},{"pmid":"27799409","id":"PMC_27799409","title":"ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism.","date":"2016","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27799409","citation_count":98,"is_preprint":false},{"pmid":"27899449","id":"PMC_27899449","title":"Deficiency of a Retinal Dystrophy Protein, Acyl-CoA Binding Domain-containing 5 (ACBD5), Impairs Peroxisomal β-Oxidation of Very-long-chain Fatty Acids.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27899449","citation_count":73,"is_preprint":false},{"pmid":"35019937","id":"PMC_35019937","title":"Regulating peroxisome-ER contacts via the ACBD5-VAPB tether by FFAT motif phosphorylation and GSK3β.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35019937","citation_count":51,"is_preprint":false},{"pmid":"25175022","id":"PMC_25175022","title":"A novel RET rearrangement (ACBD5/RET) by pericentric inversion, inv(10)(p12.1;q11.2), in papillary thyroid cancer from an atomic bomb survivor exposed to high-dose radiation.","date":"2014","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25175022","citation_count":25,"is_preprint":false},{"pmid":"30589881","id":"PMC_30589881","title":"Intracellular redistribution of neuronal peroxisomes in response to ACBD5 expression.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30589881","citation_count":22,"is_preprint":false},{"pmid":"33427402","id":"PMC_33427402","title":"First reported adult patient with retinal dystrophy and leukodystrophy caused by a novel ACBD5 variant: A case report and review of literature.","date":"2021","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33427402","citation_count":19,"is_preprint":false},{"pmid":"37414147","id":"PMC_37414147","title":"Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37414147","citation_count":11,"is_preprint":false},{"pmid":"34668366","id":"PMC_34668366","title":"Newly defined peroxisomal disease with novel ACBD5 mutation.","date":"2021","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/34668366","citation_count":11,"is_preprint":false},{"pmid":"38066620","id":"PMC_38066620","title":"Ataxia with giant axonopathy in Acbd5-deficient mice halted by adeno-associated virus gene therapy.","date":"2024","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38066620","citation_count":6,"is_preprint":false},{"pmid":"37789430","id":"PMC_37789430","title":"ACBD5-related retinal dystrophy with leukodystrophy due to novel mutations in ACBD5 and with additional features including ovarian insufficiency.","date":"2023","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/37789430","citation_count":6,"is_preprint":false},{"pmid":"39939783","id":"PMC_39939783","title":"ACOT12, a novel factor in the pathogenesis of kidney fibrosis, modulates ACBD5.","date":"2025","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39939783","citation_count":5,"is_preprint":false},{"pmid":"40672445","id":"PMC_40672445","title":"The neurological pathology of peroxisomal ACBD5 deficiency - lessons from patients and mouse models.","date":"2025","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/40672445","citation_count":4,"is_preprint":false},{"pmid":"36699790","id":"PMC_36699790","title":"Variables in the ACBD5 Gene Leading to Distinct Phenotypes: A Case Report.","date":"2022","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/36699790","citation_count":4,"is_preprint":false},{"pmid":"38841324","id":"PMC_38841324","title":"A Novel Homozygous ACBD5 Variant in an Emerging Peroxisomal Disorder Presenting with Retinal Dystrophy and a Review of the Literature.","date":"2024","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/38841324","citation_count":3,"is_preprint":false},{"pmid":"41324649","id":"PMC_41324649","title":"Local accumulation of very long-chain PUFA in plexiform layers associates with retinal dysfunction in a mouse model of peroxisomal ACBD5-deficiency.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/41324649","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.06.21.599987","title":"New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms","date":"2024-06-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.21.599987","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10870,"output_tokens":3144,"usd":0.039885,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10580,"output_tokens":3607,"usd":0.071538,"stage2_stop_reason":"end_turn"},"total_usd":0.111423,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"ACBD5 (peroxisomal membrane protein) directly interacts with ER-resident VAPA and VAPB to tether peroxisomes to the ER; depletion of either ACBD5 or VAP increases peroxisome mobility, indicating the VAP-ACBD5 complex acts as the primary ER-peroxisome tether. This tethering is required for peroxisome growth, plasmalogen phospholipid synthesis, and maintenance of cellular cholesterol levels.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/depletion, live-cell imaging of peroxisome mobility, lipid biochemistry\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and functional depletion with defined organellar and lipid phenotypes; independently replicated in two concurrent papers (PMID:28108526 and PMID:28108524)\",\n      \"pmids\": [\"28108526\", \"28108524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ACBD5 binds to VAPB via an FFAT-like motif interacting with VAPB's major sperm protein (MSP) domain; loss of ACBD5-VAPB interaction reduces peroxisome-ER associations and increases peroxisome movement, and also perturbs peroxisome membrane expansion.\",\n      \"method\": \"Co-immunoprecipitation, FFAT-motif mapping, live-cell imaging, electron microscopy of contact sites\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-level binding characterization with reciprocal Co-IP, functional ER-contact and mobility assays, replicated across two independent labs\",\n      \"pmids\": [\"28108524\", \"28108526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ACBD5 deficiency (patient mutation and CRISPR-Cas9 KO in HeLa cells) causes accumulation of very long-chain fatty acids (VLCFAs) due to impaired peroxisomal β-oxidation; the proposed mechanism is that ACBD5 sequesters C26-CoA in the cytosol to facilitate transport into peroxisomes. No effect on pexophagy was detected.\",\n      \"method\": \"CRISPR-Cas9 knockout, patient-derived fibroblasts, biochemical VLCFA measurement, pexophagy assay\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independently replicated by two concurrent papers using patient material and genome-edited cell lines with defined biochemical readouts\",\n      \"pmids\": [\"27799409\", \"27899449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ACBD5 is a peroxisomal tail-anchored membrane protein that exposes its acyl-CoA binding domain (ACBD) to the cytosol; it preferentially binds very-long-chain fatty acyl-CoAs (VLC-CoAs). Both the N-terminal ACBD and peroxisomal localization are required for efficient VLCFA β-oxidation. ACBD5 deficiency elevates cellular phospholipids containing VLCFAs without affecting peroxisome biogenesis or import of membrane/matrix proteins.\",\n      \"method\": \"Subcellular fractionation, domain mutagenesis, in vitro acyl-CoA binding assay, KO cell lines (patient fibroblasts and CRISPR HeLa), lipidomics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding assay plus domain mutagenesis plus KO phenotype in a single rigorous study\",\n      \"pmids\": [\"27899449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Peroxisome-ER contacts via the ACBD5-VAPB tether are regulated by phosphorylation: GSK3β phosphorylates sites in the flanking regions and core of the ACBD5 FFAT-like motif, altering VAPB binding and thus peroxisome-ER contact site formation. The interaction is phosphatase-sensitive.\",\n      \"method\": \"Phosphorylation site mapping (mass spectrometry), phospho-mimetic/phospho-dead mutagenesis, GSK3β inhibitor treatment, proximity ligation assay for contact sites, Co-IP\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — phosphorylation site identified by MS, functionally validated by mutagenesis and kinase inhibition with defined contact-site phenotype\",\n      \"pmids\": [\"35019937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Overexpression of ACBD5 in hippocampal neurons reduces peroxisomal long-range movements in neurites by ~70% and redistributes peroxisomes toward the cell periphery and into neurites; this effect is independent of VAPB binding, as an ACBD5 variant unable to bind VAPB produces the same redistribution, suggesting additional ACBD5-binding partners tether peroxisomes near the plasma membrane in neurons.\",\n      \"method\": \"Confocal live-cell imaging in cultured hippocampal neurons, transfection with ACBD5 wild-type and VAPB-binding-deficient mutant, quantification of peroxisome motility and distribution\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct live imaging with VAPB-binding mutant used to dissect mechanism, single lab, single cell-type system\",\n      \"pmids\": [\"30589881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACBD5 and ACBD4 interact with each other independently of VAPB binding. ACBD5 acts as the primary peroxisome-ER tether and VLCFA recruitment factor, whereas ACBD4 has regulatory functions: loss of ACBD4 increases the rate of VLCFA β-oxidation rather than decreasing it, and does not reduce peroxisome-ER contacts or cause VLCFA accumulation.\",\n      \"method\": \"Co-immunoprecipitation (ACBD4-ACBD5 interaction), KO of ACBD4 or ACBD5 in HEK293 cells, lipidomics, peroxisome-ER contact site quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for interaction plus KO phenotype with lipidomics, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37414147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In a radiation-induced papillary thyroid cancer, ACBD5 is fused to RET by pericentric inversion inv(10)(p12.1;q11.2); the resulting ACBD5-RET fusion protein activates ERK/MAPK signaling (enhanced ERK phosphorylation) and induces tumor formation in nude mouse xenografts, indicating oncogenic activity of this rearrangement.\",\n      \"method\": \"5' RACE, RT-PCR, transfection of full-length ACBD5-RET cDNA into NIH3T3 cells, Western blot for ERK phosphorylation, xenograft tumor formation assay\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional in vitro and in vivo assays for the fusion protein, but single lab and single case; finding is about a fusion gene, not native ACBD5 function\",\n      \"pmids\": [\"25175022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Acbd5-deficient mice (CRISPR Gly357* allele), VLCFA accumulation leads to deregulated cytoskeleton with reduced actin dynamics and increased neuronal filopodia (shown in neurons treated with VLCFA); AAV-mediated gene delivery of ACBD5 ameliorated gait phenotypes, giant axonopathy, myelination defects, and astrocyte reactivity.\",\n      \"method\": \"CRISPR/Cas9 mouse model, lipidomics, proteomics, functional actin dynamics assay in VLCFA-treated neurons, AAV gene therapy rescue experiment\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with rescue experiment and mechanistic follow-up in neurons, single lab\",\n      \"pmids\": [\"38066620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In ACBD5-deficient mouse retina, VLC-PUFAs specifically accumulate in phosphatidylcholines of the inner retinal plexiform layers (OPL to IPL) rather than in photoreceptor outer segments; photoreceptor ribbon synapses at the OPL show ultrastructural degeneration, and ffERG reveals severe functional dysregulation of retinal signal transduction, pointing to cell-type-specific disruption of lipid homeostasis as the pathogenic mechanism.\",\n      \"method\": \"Immunofluorescence microscopy, electron microscopy, full-field electroretinography, MALDI MS imaging-based spatial lipidomics\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal methods in a mouse model, but single lab and mechanistic interpretation is correlative\",\n      \"pmids\": [\"41324649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Phylogenetic and experimental analyses show that ACBD5's peroxisome-ER tethering function via the FFAT motif is conserved in vertebrates and in Drosophila (where the single ACBD4/5-like protein uses its FFAT motif to tether peroxisomes to the ER via Dm_Vap33); the filamentous fungus Ustilago maydis ACBD4/5-like protein lacks a FFAT motif and does not interact with Um_Vap33, indicating the tethering function was acquired during animal evolution.\",\n      \"method\": \"Phylogenetic analysis, FFAT motif mutagenesis, Co-IP (Drosophila and fungal proteins with VAP orthologs), RNAi depletion of Dm_Acbd4/5 with peroxisome distribution readout\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, Co-IP and RNAi in non-mammalian organisms; mechanistic conclusions about human ACBD5 are indirect\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ACBD5 is a peroxisomal tail-anchored membrane protein that exposes its acyl-CoA binding domain to the cytosol, where it captures very-long-chain fatty acyl-CoAs (VLC-CoAs) to facilitate their import into peroxisomes for β-oxidation; it simultaneously tethers peroxisomes to the ER by binding ER-resident VAPA/VAPB through an FFAT-like motif—an interaction regulated by GSK3β-mediated phosphorylation—thereby enabling lipid exchange, plasmalogen synthesis, cholesterol homeostasis, and peroxisome membrane expansion, while also interacting with paralog ACBD4 at the peroxisome-ER interface in a regulatory capacity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACBD5 is a peroxisomal tail-anchored membrane protein that couples very-long-chain fatty acid (VLCFA) metabolism to inter-organelle membrane contact, exposing an N-terminal acyl-CoA binding domain (ACBD) to the cytosol where it preferentially captures very-long-chain fatty acyl-CoAs and channels them into peroxisomes for β-oxidation; loss of ACBD5 or its ACBD causes cellular accumulation of VLCFAs and VLCFA-containing phospholipids without disrupting peroxisome biogenesis or protein import [#2, #3]. Independently of this metabolic role, ACBD5 serves as the primary ER–peroxisome tether: through an FFAT-like motif it binds the MSP domain of the ER-resident proteins VAPA and VAPB, and loss of this interaction reduces peroxisome–ER contacts, increases peroxisome mobility, and impairs peroxisome growth, plasmalogen synthesis, and cholesterol homeostasis [#0, #1]. Tether formation is dynamically controlled by GSK3β phosphorylation of the FFAT-like motif and its flanking regions, which modulates VAPB binding in a phosphatase-sensitive manner [#4]. ACBD5 also interacts with its paralog ACBD4 in a VAPB-independent fashion, with ACBD4 exerting a regulatory rather than tethering role over VLCFA β-oxidation [#6]. Functionally, ACBD5 deficiency drives neurological and retinal pathology: in mouse models, VLCFA accumulation deregulates actin dynamics and produces axonopathy, myelination defects, and cell-type-specific retinal lipid accumulation with synaptic degeneration, and AAV-mediated ACBD5 delivery ameliorates the neurological phenotypes [#8, #9]. A radiation-induced ACBD5-RET gene fusion activates ERK/MAPK signaling and is oncogenic, but this reflects the fusion product rather than native ACBD5 function [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Before native ACBD5 function was defined, a chromosomal rearrangement revealed the locus could contribute an oncogenic fusion, establishing ACBD5 as a fusion partner driving aberrant signaling.\",\n      \"evidence\": \"5' RACE/RT-PCR identification of an ACBD5-RET fusion, transfection into NIH3T3, ERK phosphorylation Western blot, and xenograft tumor formation\",\n      \"pmids\": [\"25175022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Concerns the ACBD5-RET fusion protein, not native ACBD5 biology\", \"Single case and single lab\", \"Does not address normal cellular function of ACBD5\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"It was unknown how ACBD5 contributes to lipid metabolism; demonstrating that it is a peroxisomal tail-anchored protein with a cytosol-facing ACBD that binds VLC-CoAs and is required for VLCFA β-oxidation established ACBD5 as a substrate-recruitment factor for peroxisomal fatty acid degradation.\",\n      \"evidence\": \"Subcellular fractionation, domain mutagenesis, in vitro acyl-CoA binding, CRISPR and patient-derived KO cells, lipidomics, and VLCFA biochemistry\",\n      \"pmids\": [\"27799409\", \"27899449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of how captured VLC-CoAs cross the peroxisomal membrane not resolved\", \"Whether ACBD5 hands off substrate to a specific transporter unknown\", \"No structural model of the ACBD–acyl-CoA interaction\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The molecular basis of ER–peroxisome contacts was unclear; identifying ACBD5 as the FFAT-motif partner of ER VAPA/VAPB established the ACBD5–VAP complex as the primary ER–peroxisome tether required for peroxisome growth and lipid homeostasis.\",\n      \"evidence\": \"Reciprocal Co-IP, FFAT-motif mapping, knockdown, live-cell peroxisome mobility imaging, electron microscopy of contact sites, and lipid biochemistry, replicated across two concurrent papers\",\n      \"pmids\": [\"28108526\", \"28108524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How tethering mechanistically enables plasmalogen and cholesterol homeostasis not fully resolved\", \"Whether lipid transfer occurs directly at the contact not shown\", \"Relationship between the tethering and VLC-CoA capture functions not integrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether ACBD5 tethering relied solely on VAPB was untested; showing that ACBD5 overexpression redistributes neuronal peroxisomes independently of VAPB binding implied additional, undefined ACBD5 partners anchor peroxisomes in neurons.\",\n      \"evidence\": \"Confocal live-cell imaging in hippocampal neurons with wild-type and VAPB-binding-deficient ACBD5, quantifying peroxisome motility and distribution\",\n      \"pmids\": [\"30589881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The proposed additional peripheral tethering partners are not identified\", \"Single cell-type, overexpression-based system\", \"Physiological relevance of the redistribution not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"How ER–peroxisome contacts are regulated was unknown; identifying GSK3β phosphorylation of the ACBD5 FFAT-like motif as a switch for VAPB binding established a signaling mechanism controlling contact-site dynamics.\",\n      \"evidence\": \"Mass spectrometry phospho-site mapping, phospho-mimetic/dead mutagenesis, GSK3β inhibition, proximity ligation assay, and Co-IP\",\n      \"pmids\": [\"35019937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating GSK3β toward ACBD5 unknown\", \"Whether phosphorylation also affects VLC-CoA capture not tested\", \"Counteracting phosphatase not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The role of the ACBD5 paralog ACBD4 was unclear; showing ACBD4 binds ACBD5 independently of VAPB and that its loss increases rather than decreases VLCFA β-oxidation established ACBD4 as a regulatory rather than tethering factor.\",\n      \"evidence\": \"Co-IP for ACBD4-ACBD5 interaction, KO of each gene in HEK293, lipidomics, and contact-site quantification\",\n      \"pmids\": [\"37414147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ACBD4 restrains β-oxidation not defined\", \"Stoichiometry of an ACBD4-ACBD5 complex unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The link between ACBD5 loss and neuropathology was undefined in vivo; an Acbd5-deficient mouse showed VLCFA-driven cytoskeletal deregulation, axonopathy, and myelination defects rescuable by AAV-delivered ACBD5, establishing causal disease mechanism and therapeutic proof-of-concept.\",\n      \"evidence\": \"CRISPR Gly357* mouse, lipidomics, proteomics, actin dynamics assay in VLCFA-treated neurons, and AAV gene-therapy rescue\",\n      \"pmids\": [\"38066620\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between VLCFA accumulation and actin deregulation not fully mechanistic\", \"Single lab\", \"Long-term durability of AAV rescue not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Why ACBD5 loss causes retinal disease was unclear; spatial lipidomics revealing cell-type-specific VLC-PUFA accumulation in inner retinal layers with ribbon-synapse degeneration established a localized lipid-homeostasis defect as the retinal pathogenic mechanism.\",\n      \"evidence\": \"Immunofluorescence, electron microscopy, full-field electroretinography, and MALDI MS imaging spatial lipidomics in ACBD5-deficient mouse retina\",\n      \"pmids\": [\"41324649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between lipid accumulation and synaptic degeneration is correlative\", \"Why specific retinal layers are affected unexplained\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ACBD5's VLC-CoA capture and ER tethering functions are mechanistically integrated, and the identity of the non-VAP partners that anchor peroxisomes in neurons, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of ACBD5 or its complexes\", \"Mechanism of VLC-CoA membrane translocation downstream of capture unknown\", \"Additional neuronal tethering partners unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VAPA\", \"VAPB\", \"ACBD4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}