{"gene":"PLIN4","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2003,"finding":"PLIN4 (S3-12) coats nascent lipid droplets in adipocytes in a fatty acid- and insulin-dependent manner requiring triacylglycerol synthesis; prior to lipid loading it is distributed diffusely in the cytoplasm, and upon oleate treatment it rapidly localizes to ~500-nm peripheral lipid droplet structures.","method":"Immunofluorescence microscopy of 3T3-L1 adipocytes with oleate supplementation; inhibitor of triacylglycerol synthesis blocked droplet formation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean localization experiment with functional pharmacological controls replicated in follow-up study","pmids":["12840023"],"is_preprint":false},{"year":2005,"finding":"PLIN4 (S3-12), together with adipophilin and TIP47, constitutes a coat on nascent lipid droplets in adipocytes; upon oleate treatment these proteins redistribute from cytosolic fractions to the lipid droplet fraction, forming a ready reservoir for rapid triacylglycerol packaging.","method":"Immunofluorescence microscopy and subcellular fractionation of 3T3-L1 adipocytes; cycloheximide treatment showed pre-existing coat protein pools are sufficient","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — orthogonal fractionation and imaging methods, replication of earlier findings with mechanistic extension","pmids":["15731108"],"is_preprint":false},{"year":2004,"finding":"PLIN4 (S3-12) is a direct transcriptional target of PPARγ; the S3-12 promoter contains three evolutionarily conserved PPAR response elements that drive adipose-specific expression.","method":"Promoter characterization, reporter assays, and gene expression analysis in adipocytes and Zucker rats","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — promoter functional analysis with conserved PPRE identification, replicated in vivo","pmids":["15111493"],"is_preprint":false},{"year":2013,"finding":"Plin4 deficiency in mice downregulates Plin5 mRNA (~38%) and protein (~87%) specifically in the heart, reduces cardiac triacylglycerol content, and protects against cardiac steatosis induced by fasting, high-fat diet, or leptin deficiency, without affecting body composition or adipose development.","method":"Plin4−/− mouse generated by gene targeting; echocardiography, lipid quantification, qPCR, western blot across tissues","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse with defined tissue-specific phenotype and molecular readouts across multiple dietary challenges","pmids":["23423172"],"is_preprint":false},{"year":2018,"finding":"Plin4-dependent lipid droplet accumulation in dopaminergic neurons inhibits mitophagy via the parkin-poly-Ub-p62 pathway; knockdown of Plin4 reduces lipid droplet storage, restores autophagy flux, alleviates mitochondrial damage, and promotes neuronal survival in the MPTP/p mouse model of Parkinson's disease.","method":"Plin4 siRNA knockdown in SH-SY5Y cells and primary dopaminergic neurons; autophagy inhibitor rescue experiment; MPTP/p mouse model with immunohistochemistry for TH-ir neurons","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined pathway placement (parkin-p62 mitophagy axis) in both in vivo and in vitro models, single lab","pmids":["29967574"],"is_preprint":false},{"year":2022,"finding":"SH2B1 binds HSC70 and promotes HSC70-mediated lysosomal translocation and degradation of PLIN4, thereby suppressing lipid peroxidation stress and neuronal apoptosis in the MPTP mouse model of Parkinson's disease.","method":"Co-IP of SH2B1 with HSC70; Sh2b1 KO and neuron-specific overexpression mice; AAV-mediated HSC70 rescue in WT and Sh2b1-KO; MPP+-treated SH-SY5Y cells","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal binding demonstrated, in vivo genetic rescue experiment, but single lab","pmids":["35390677"],"is_preprint":false},{"year":2024,"finding":"Senp7 deSUMOylates Plin4 to promote its localization to lipid droplets; loss of Senp7 results in increased Plin4 SUMOylation, failure of Plin4 to localize to lipid droplets, smaller lipid droplet size, and reduced white adipose tissue mass.","method":"Conventional and adipocyte-specific Senp7 KO mice; lipid droplet morphology analysis; biochemical deSUMOylation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined molecular mechanism (deSUMOylation) and lipid droplet localization phenotype, single lab","pmids":["38677512"],"is_preprint":false},{"year":2024,"finding":"METTL3/METTL14-dependent m6A RNA modification upregulates PLIN4 expression in Leydig cells exposed to cadmium; elevated PLIN4 promotes lipid droplet deposition and ferroptosis, reducing testosterone synthesis; Plin4 siRNA reverses these effects.","method":"Plin4 siRNA in testicular Leydig cells; METTL3/METTL14 inhibitor (S-adenosylhomocysteine); measurement of Fe2+, lipid droplets, testosterone levels; in vivo cadmium exposure model","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with defined upstream regulatory mechanism and downstream ferroptosis pathway, single lab","pmids":["39173539"],"is_preprint":false},{"year":2025,"finding":"Plin4 deficiency in diet-obese female mice reduces hepatic triacylglycerol accumulation and endoplasmic reticulum stress markers downstream of PERK, and elevates adipose tissue inflammation (macrophage infiltration, crown-like structures) without changing adipocyte size.","method":"Plin4−/− mouse on Western diet; hepatic lipid quantification, ER stress marker expression, adipose tissue histology and macrophage marker expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with tissue-specific molecular readouts, but mechanistic link between Plin4 and ER stress is correlative","pmids":["41391763"],"is_preprint":false},{"year":2019,"finding":"PLIN4 coats lipid droplets in chemoresistant triple-negative breast cancer cells; PLIN4 knockdown destabilizes these lipid droplets and reduces cell viability, demonstrating that PLIN4 is functionally required for lipid droplet maintenance in the chemoresistant state.","method":"PLIN4 siRNA knockdown in MDA-MB-436 chemoresistant cells; lipid droplet imaging; cell viability assays; validation in clinical TNBC cohort","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 3 — KD with defined cellular phenotype (lipid droplet destabilization) but limited mechanistic depth","pmids":["31537618"],"is_preprint":false},{"year":2025,"finding":"The PLIN4 repetitive region (~1000 aa amphipathic helix of tandem 33-aa repeats) forms amyloid fibrils in vitro; repeat expansion associated with myopathy accelerates fibril formation; lipid droplet binding attenuates aggregation, indicating that LD association and amyloid self-assembly are competing states for PLIN4.","method":"Cryo-EM and atomic force microscopy of purified PLIN4 repeat fragments; fibrillation kinetics comparing normal vs. expanded repeats; cell-based lipid droplet binding assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — cryo-EM structural characterization of fibrils in vitro with mechanistic competition assay, but preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2024,"finding":"PLIN4 upregulation by sevoflurane in hippocampal neurons promotes ferroptosis by inhibiting the Hippo signaling pathway; PLIN4 knockdown reduces ferroptosis and partially restores Hippo pathway activity.","method":"PLIN4 knockdown/overexpression by vector transfection in HT22 cells; RT-qPCR, immunostaining, western blot for Hippo pathway components; transmission electron microscopy; Fe2+ measurement","journal":"Neurotoxicology","confidence":"Low","confidence_rationale":"Tier 3 — KD with pathway placement but mechanistic link between PLIN4 and Hippo pathway is correlative, single lab","pmids":["39182851"],"is_preprint":false}],"current_model":"PLIN4 is a PPARγ-regulated amphipathic helix protein that coats nascent lipid droplets in adipocytes and other cell types, where its lipid droplet localization is controlled post-translationally by SENP7-mediated deSUMOylation; at the organismal level it regulates cardiac lipid storage partly by controlling Plin5 expression, and in neurons excess PLIN4-dependent lipid droplet accumulation inhibits mitophagy via the parkin-p62 axis and promotes ferroptosis, while SH2B1 counteracts this by recruiting HSC70 to drive lysosomal degradation of PLIN4; repeat expansion in PLIN4 causes autosomal dominant vacuolar myopathy, mechanistically linked to accelerated amyloid fibril formation by the repetitive amphipathic helix domain."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that PLIN4 is a lipid droplet coat protein resolved its subcellular function: it redistributes from the cytoplasm to nascent peripheral lipid droplets upon fatty acid loading, in a triacylglycerol synthesis–dependent manner.","evidence":"Immunofluorescence of oleate-treated 3T3-L1 adipocytes with triacylglycerol synthesis inhibitor","pmids":["12840023"],"confidence":"High","gaps":["Mechanism by which PLIN4 selectively targets nascent versus mature lipid droplets was not defined","Structural basis of the amphipathic helix–lipid droplet interaction not resolved"]},{"year":2004,"claim":"Identifying PLIN4 as a direct PPARγ transcriptional target explained its adipose-enriched expression and linked it to the master adipogenic program.","evidence":"Promoter-reporter assays identifying three conserved PPREs; expression analysis in adipocytes and Zucker rats","pmids":["15111493"],"confidence":"High","gaps":["Whether additional transcription factors cooperate with PPARγ at the PLIN4 locus was not tested","Regulation in non-adipose tissues not addressed"]},{"year":2005,"claim":"Demonstrating that PLIN4 belongs to a pre-existing cytosolic reservoir of coat proteins (with adipophilin and TIP47) that package triacylglycerol without new protein synthesis established a rapid-response lipid storage mechanism.","evidence":"Subcellular fractionation and cycloheximide treatment of oleate-loaded 3T3-L1 adipocytes","pmids":["15731108"],"confidence":"High","gaps":["Functional redundancy or hierarchy among the three coat proteins was not resolved","Post-translational signals controlling redistribution were unknown"]},{"year":2013,"claim":"The Plin4 knockout mouse revealed an unexpected tissue-specific role in the heart: Plin4 loss reduced cardiac triacylglycerol and dramatically decreased Plin5 expression, linking PLIN4 to cardiac lipid homeostasis beyond a simple coat function.","evidence":"Gene-targeted Plin4−/− mice subjected to fasting, high-fat diet, and leptin-deficiency challenges with cardiac lipid quantification and qPCR","pmids":["23423172"],"confidence":"High","gaps":["Mechanism by which Plin4 controls Plin5 transcription in the heart is unknown","Whether cardiac protection from steatosis translates to functional cardiac benefit was not assessed"]},{"year":2018,"claim":"Placing PLIN4-dependent lipid droplet accumulation upstream of impaired parkin–ubiquitin–p62 mitophagy in dopaminergic neurons provided a mechanistic link between lipid storage and neurodegeneration in a Parkinson's disease model.","evidence":"Plin4 siRNA in SH-SY5Y cells and primary neurons; MPTP/p mouse model with TH-neuron quantification","pmids":["29967574"],"confidence":"Medium","gaps":["Whether PLIN4-coated lipid droplets physically sequester parkin or p62 was not shown","Not independently replicated","Causal direction between lipid droplet excess and mitophagy inhibition not fully dissected"]},{"year":2019,"claim":"Demonstrating that PLIN4 is required for lipid droplet stability and viability in chemoresistant triple-negative breast cancer cells extended its functional significance to cancer biology.","evidence":"PLIN4 siRNA in MDA-MB-436 chemoresistant cells with lipid droplet imaging and viability assays","pmids":["31537618"],"confidence":"Medium","gaps":["Mechanistic basis of chemoresistance dependence on PLIN4-coated lipid droplets was not elucidated","Limited to a single cell line"]},{"year":2022,"claim":"Identifying SH2B1 as a recruiter of HSC70 that drives lysosomal degradation of PLIN4 defined a post-translational clearance pathway and explained how PLIN4 protein levels are constrained to prevent lipid peroxidation and neuronal apoptosis.","evidence":"Co-IP of SH2B1–HSC70; Sh2b1 KO and neuron-specific overexpression in MPTP mice; AAV-HSC70 rescue","pmids":["35390677"],"confidence":"Medium","gaps":["Direct ubiquitin or chaperone-mediated autophagy signals on PLIN4 were not mapped","Whether this degradation pathway operates in non-neuronal tissues is untested"]},{"year":2024,"claim":"Showing that SENP7-mediated deSUMOylation is required for PLIN4 lipid droplet targeting resolved a key post-translational switch: SUMOylated PLIN4 fails to coat droplets, resulting in smaller droplets and reduced adipose mass.","evidence":"Conventional and adipocyte-specific Senp7 KO mice; biochemical deSUMOylation assay","pmids":["38677512"],"confidence":"Medium","gaps":["Specific SUMO-modified residues on PLIN4 were not identified","Whether SUMOylation affects PLIN4 stability or only localization is unclear","Not independently replicated"]},{"year":2024,"claim":"Demonstrating that PLIN4 upregulation promotes ferroptosis in Leydig cells (via cadmium/m6A pathway) and hippocampal neurons (via sevoflurane) broadened PLIN4's pathological roles to iron-dependent cell death across tissues.","evidence":"Plin4 siRNA in Leydig cells with Fe²⁺ and lipid droplet quantification; PLIN4 KD/OE in HT22 hippocampal cells with ferroptosis markers","pmids":["39173539","39182851"],"confidence":"Medium","gaps":["Direct mechanism linking PLIN4/lipid droplets to lipid peroxidation and iron metabolism is not defined","Hippo pathway connection (PMID:39182851) is correlative with low confidence"]},{"year":2025,"claim":"Plin4 knockout in diet-obese female mice revealed a hepatoprotective role: Plin4 loss reduced hepatic triacylglycerol and PERK-dependent ER stress, but increased adipose inflammation, suggesting tissue-opposing metabolic functions.","evidence":"Plin4−/− mice on Western diet; hepatic lipid quantification, ER stress markers, adipose histology","pmids":["41391763"],"confidence":"Medium","gaps":["Link between PLIN4 and PERK pathway is correlative","Mechanism of increased adipose inflammation in the absence of Plin4 is unknown","Sex-specific effects not tested in males"]},{"year":2025,"claim":"Structural demonstration that the PLIN4 tandem 33-aa amphipathic helix repeat domain forms amyloid fibrils—accelerated by disease-associated repeat expansion—and that lipid droplet binding competes with fibrillation provided a molecular mechanism for PLIN4 repeat-expansion vacuolar myopathy.","evidence":"(preprint) Cryo-EM, atomic force microscopy of purified repeat fragments; fibrillation kinetics; cell-based lipid droplet binding competition assay","pmids":[],"confidence":"Medium","gaps":["Not yet peer-reviewed","In vivo fibril formation in patient muscle not demonstrated","Repeat expansion threshold for clinical disease not defined"]},{"year":null,"claim":"The precise structural basis by which PLIN4 amphipathic helices coat lipid droplet monolayers, the SUMO acceptor sites controlling its localization, the mechanism linking PLIN4-coated droplets to ferroptosis and mitophagy inhibition, and the in vivo relevance of amyloid fibril formation in myopathy remain open questions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of PLIN4 on a lipid droplet surface","SUMO modification sites unmapped","Causal mechanism connecting lipid droplet coating to iron-dependent cell death not established","Patient tissue confirmation of amyloid fibrils absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,6,10]}],"localization":[{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[0,1,6,9,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,3,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,7]}],"complexes":[],"partners":["SENP7","SH2B1","HSPA8","PLIN5"],"other_free_text":[]},"mechanistic_narrative":"PLIN4 is a PPARγ-regulated lipid droplet coat protein whose tandem 33-amino-acid amphipathic helix repeats enable rapid, reversible association with nascent triacylglycerol-rich lipid droplets in adipocytes and other cell types [PMID:12840023, PMID:15111493]. Its lipid droplet targeting is controlled post-translationally by SENP7-mediated deSUMOylation, and in the cytosol PLIN4 is turned over via HSC70-dependent lysosomal degradation promoted by SH2B1 [PMID:38677512, PMID:35390677]. At the organismal level, Plin4 deficiency reduces cardiac and hepatic triacylglycerol storage—partly by downregulating Plin5 in the heart—and modulates ER stress and adipose inflammation under dietary stress, while excess PLIN4-dependent lipid droplet accumulation in neurons inhibits parkin–p62-mediated mitophagy and promotes ferroptosis [PMID:23423172, PMID:41391763, PMID:29967574, PMID:39173539]. The ~1000-amino-acid repetitive amphipathic helix domain can form amyloid fibrils in vitro, and repeat expansion linked to autosomal dominant vacuolar myopathy accelerates this fibrillation, with lipid droplet binding and amyloid self-assembly representing competing fates for the protein [PMID:12840023]."},"prefetch_data":{"uniprot":{"accession":"Q96Q06","full_name":"Perilipin-4","aliases":["Adipocyte protein S3-12"],"length_aa":1371,"mass_kda":135.9,"function":"May play a role in triacylglycerol packaging into adipocytes. May function as a coat protein involved in the biogenesis of lipid droplets (By similarity)","subcellular_location":"Cell membrane; Cytoplasm; Lipid droplet","url":"https://www.uniprot.org/uniprotkb/Q96Q06/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLIN4","classification":"Not Classified","n_dependent_lines":27,"n_total_lines":1208,"dependency_fraction":0.022350993377483443},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLIN4","total_profiled":1310},"omim":[{"mim_id":"613247","title":"PERILIPIN 4; PLIN4","url":"https://www.omim.org/entry/613247"},{"mim_id":"601846","title":"MYOPATHY WITH RIMMED UBIQUITIN-POSITIVE AUTOPHAGIC VACUOLATION, AUTOSOMAL DOMINANT; MRUPAV","url":"https://www.omim.org/entry/601846"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Enhanced"},{"location":"Lipid droplets","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":715.6},{"tissue":"breast","ntpm":303.4},{"tissue":"skeletal muscle","ntpm":235.5}],"url":"https://www.proteinatlas.org/search/PLIN4"},"hgnc":{"alias_symbol":["S3-12"],"prev_symbol":["KIAA1881"]},"alphafold":{"accession":"Q96Q06","domains":[{"cath_id":"1.20.120.340","chopping":"1185-1226_1250-1344","consensus_level":"medium","plddt":78.0781,"start":1185,"end":1344}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q06","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q06-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96Q06-F1-predicted_aligned_error_v6.png","plddt_mean":34.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLIN4","jax_strain_url":"https://www.jax.org/strain/search?query=PLIN4"},"sequence":{"accession":"Q96Q06","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96Q06.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96Q06/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96Q06"}},"corpus_meta":[{"pmid":"15731108","id":"PMC_15731108","title":"S3-12, Adipophilin, and TIP47 package lipid in adipocytes.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15731108","citation_count":291,"is_preprint":false},{"pmid":"12840023","id":"PMC_12840023","title":"Adipocyte protein S3-12 coats nascent lipid droplets.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12840023","citation_count":190,"is_preprint":false},{"pmid":"15111493","id":"PMC_15111493","title":"Adipose tissue expression of the lipid droplet-associating proteins S3-12 and perilipin is controlled by peroxisome proliferator-activated receptor-gamma.","date":"2004","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/15111493","citation_count":183,"is_preprint":false},{"pmid":"31537618","id":"PMC_31537618","title":"A Unique Morphological Phenotype in Chemoresistant Triple-Negative Breast Cancer Reveals Metabolic Reprogramming and PLIN4 Expression as a Molecular Vulnerability.","date":"2019","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/31537618","citation_count":90,"is_preprint":false},{"pmid":"23423172","id":"PMC_23423172","title":"Inactivation of Plin4 downregulates Plin5 and reduces cardiac lipid accumulation in mice.","date":"2013","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23423172","citation_count":82,"is_preprint":false},{"pmid":"29967574","id":"PMC_29967574","title":"Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson's Disease.","date":"2018","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29967574","citation_count":73,"is_preprint":false},{"pmid":"39173539","id":"PMC_39173539","title":"Plin4 exacerbates cadmium-decreased testosterone level via inducing ferroptosis in testicular Leydig cells.","date":"2024","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/39173539","citation_count":29,"is_preprint":false},{"pmid":"35390677","id":"PMC_35390677","title":"Neuronal SH2B1 attenuates apoptosis in an MPTP mouse model of Parkinson's disease via promoting PLIN4 degradation.","date":"2022","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/35390677","citation_count":22,"is_preprint":false},{"pmid":"29361938","id":"PMC_29361938","title":"Long-term effects of Garcinia cambogia/Glucomannan on weight loss in people with obesity, PLIN4, FTO and Trp64Arg polymorphisms.","date":"2018","source":"BMC complementary and alternative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29361938","citation_count":22,"is_preprint":false},{"pmid":"36985364","id":"PMC_36985364","title":"Probiotic Bifidobacterium breve MCC1274 Protects against Oxidative Stress and Neuronal Lipid Droplet Formation via PLIN4 Gene Regulation.","date":"2023","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/36985364","citation_count":18,"is_preprint":false},{"pmid":"38677512","id":"PMC_38677512","title":"Senp7 deficiency impairs lipid droplets maturation in white adipose tissues via Plin4 deSUMOylation.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38677512","citation_count":11,"is_preprint":false},{"pmid":"36151849","id":"PMC_36151849","title":"Subsarcolemmal and cytoplasmic p62 positivity and rimmed vacuoles are distinctive for PLIN4-myopathy.","date":"2022","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/36151849","citation_count":9,"is_preprint":false},{"pmid":"30507998","id":"PMC_30507998","title":"Effects of polymorphisms in APOB, APOE, HSD11β1, PLIN4, and ADIPOQ genes on lipid profile and anthropometric variables related to obesity in children and adolescents.","date":"2018","source":"Genetics and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30507998","citation_count":7,"is_preprint":false},{"pmid":"39182851","id":"PMC_39182851","title":"Sevoflurane promotes neuronal ferroptosis via upregulation of PLIN4 to modulate the hippo signaling pathway.","date":"2024","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/39182851","citation_count":6,"is_preprint":false},{"pmid":"41053121","id":"PMC_41053121","title":"Plin4 modulates lipid droplet accumulation and ferroptosis in neurons exposed to benzo[a]pyrene.","date":"2025","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41053121","citation_count":1,"is_preprint":false},{"pmid":"40693562","id":"PMC_40693562","title":"Repeat Expansions in PLIN4 Cause Autosomal Dominant Vacuolar Myopathy With Sarcolemmal Features.","date":"2025","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40693562","citation_count":0,"is_preprint":false},{"pmid":"41391763","id":"PMC_41391763","title":"Elevated adipose inflammation, but reduced hepatic triacylglycerol storage in diet-induced obese Plin4-/- mice.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41391763","citation_count":0,"is_preprint":false},{"pmid":"30293593","id":"PMC_30293593","title":"Moderating effect of PLIN4 genetic variant on impulsivity traits in 5-year-old-children born small for gestational age.","date":"2018","source":"Prostaglandins, leukotrienes, and essential fatty acids","url":"https://pubmed.ncbi.nlm.nih.gov/30293593","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.22.25329156","title":"Genomic characterization of normal and aberrant human milk production","date":"2025-06-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.22.25329156","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.03.657256","title":"Perilipin 4 repetitive region forms amyloid fibrils promoted by a genetic expansion found in myopathy patients","date":"2025-06-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.03.657256","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10914,"output_tokens":2923,"usd":0.038294},"stage2":{"model":"claude-opus-4-6","input_tokens":6282,"output_tokens":3061,"usd":0.161903},"total_usd":0.200197,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"PLIN4 (S3-12) coats nascent lipid droplets in adipocytes in a fatty acid- and insulin-dependent manner requiring triacylglycerol synthesis; prior to lipid loading it is distributed diffusely in the cytoplasm, and upon oleate treatment it rapidly localizes to ~500-nm peripheral lipid droplet structures.\",\n      \"method\": \"Immunofluorescence microscopy of 3T3-L1 adipocytes with oleate supplementation; inhibitor of triacylglycerol synthesis blocked droplet formation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean localization experiment with functional pharmacological controls replicated in follow-up study\",\n      \"pmids\": [\"12840023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PLIN4 (S3-12), together with adipophilin and TIP47, constitutes a coat on nascent lipid droplets in adipocytes; upon oleate treatment these proteins redistribute from cytosolic fractions to the lipid droplet fraction, forming a ready reservoir for rapid triacylglycerol packaging.\",\n      \"method\": \"Immunofluorescence microscopy and subcellular fractionation of 3T3-L1 adipocytes; cycloheximide treatment showed pre-existing coat protein pools are sufficient\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal fractionation and imaging methods, replication of earlier findings with mechanistic extension\",\n      \"pmids\": [\"15731108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PLIN4 (S3-12) is a direct transcriptional target of PPARγ; the S3-12 promoter contains three evolutionarily conserved PPAR response elements that drive adipose-specific expression.\",\n      \"method\": \"Promoter characterization, reporter assays, and gene expression analysis in adipocytes and Zucker rats\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — promoter functional analysis with conserved PPRE identification, replicated in vivo\",\n      \"pmids\": [\"15111493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Plin4 deficiency in mice downregulates Plin5 mRNA (~38%) and protein (~87%) specifically in the heart, reduces cardiac triacylglycerol content, and protects against cardiac steatosis induced by fasting, high-fat diet, or leptin deficiency, without affecting body composition or adipose development.\",\n      \"method\": \"Plin4−/− mouse generated by gene targeting; echocardiography, lipid quantification, qPCR, western blot across tissues\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse with defined tissue-specific phenotype and molecular readouts across multiple dietary challenges\",\n      \"pmids\": [\"23423172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Plin4-dependent lipid droplet accumulation in dopaminergic neurons inhibits mitophagy via the parkin-poly-Ub-p62 pathway; knockdown of Plin4 reduces lipid droplet storage, restores autophagy flux, alleviates mitochondrial damage, and promotes neuronal survival in the MPTP/p mouse model of Parkinson's disease.\",\n      \"method\": \"Plin4 siRNA knockdown in SH-SY5Y cells and primary dopaminergic neurons; autophagy inhibitor rescue experiment; MPTP/p mouse model with immunohistochemistry for TH-ir neurons\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined pathway placement (parkin-p62 mitophagy axis) in both in vivo and in vitro models, single lab\",\n      \"pmids\": [\"29967574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SH2B1 binds HSC70 and promotes HSC70-mediated lysosomal translocation and degradation of PLIN4, thereby suppressing lipid peroxidation stress and neuronal apoptosis in the MPTP mouse model of Parkinson's disease.\",\n      \"method\": \"Co-IP of SH2B1 with HSC70; Sh2b1 KO and neuron-specific overexpression mice; AAV-mediated HSC70 rescue in WT and Sh2b1-KO; MPP+-treated SH-SY5Y cells\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding demonstrated, in vivo genetic rescue experiment, but single lab\",\n      \"pmids\": [\"35390677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Senp7 deSUMOylates Plin4 to promote its localization to lipid droplets; loss of Senp7 results in increased Plin4 SUMOylation, failure of Plin4 to localize to lipid droplets, smaller lipid droplet size, and reduced white adipose tissue mass.\",\n      \"method\": \"Conventional and adipocyte-specific Senp7 KO mice; lipid droplet morphology analysis; biochemical deSUMOylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined molecular mechanism (deSUMOylation) and lipid droplet localization phenotype, single lab\",\n      \"pmids\": [\"38677512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3/METTL14-dependent m6A RNA modification upregulates PLIN4 expression in Leydig cells exposed to cadmium; elevated PLIN4 promotes lipid droplet deposition and ferroptosis, reducing testosterone synthesis; Plin4 siRNA reverses these effects.\",\n      \"method\": \"Plin4 siRNA in testicular Leydig cells; METTL3/METTL14 inhibitor (S-adenosylhomocysteine); measurement of Fe2+, lipid droplets, testosterone levels; in vivo cadmium exposure model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with defined upstream regulatory mechanism and downstream ferroptosis pathway, single lab\",\n      \"pmids\": [\"39173539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Plin4 deficiency in diet-obese female mice reduces hepatic triacylglycerol accumulation and endoplasmic reticulum stress markers downstream of PERK, and elevates adipose tissue inflammation (macrophage infiltration, crown-like structures) without changing adipocyte size.\",\n      \"method\": \"Plin4−/− mouse on Western diet; hepatic lipid quantification, ER stress marker expression, adipose tissue histology and macrophage marker expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with tissue-specific molecular readouts, but mechanistic link between Plin4 and ER stress is correlative\",\n      \"pmids\": [\"41391763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLIN4 coats lipid droplets in chemoresistant triple-negative breast cancer cells; PLIN4 knockdown destabilizes these lipid droplets and reduces cell viability, demonstrating that PLIN4 is functionally required for lipid droplet maintenance in the chemoresistant state.\",\n      \"method\": \"PLIN4 siRNA knockdown in MDA-MB-436 chemoresistant cells; lipid droplet imaging; cell viability assays; validation in clinical TNBC cohort\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — KD with defined cellular phenotype (lipid droplet destabilization) but limited mechanistic depth\",\n      \"pmids\": [\"31537618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The PLIN4 repetitive region (~1000 aa amphipathic helix of tandem 33-aa repeats) forms amyloid fibrils in vitro; repeat expansion associated with myopathy accelerates fibril formation; lipid droplet binding attenuates aggregation, indicating that LD association and amyloid self-assembly are competing states for PLIN4.\",\n      \"method\": \"Cryo-EM and atomic force microscopy of purified PLIN4 repeat fragments; fibrillation kinetics comparing normal vs. expanded repeats; cell-based lipid droplet binding assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structural characterization of fibrils in vitro with mechanistic competition assay, but preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLIN4 upregulation by sevoflurane in hippocampal neurons promotes ferroptosis by inhibiting the Hippo signaling pathway; PLIN4 knockdown reduces ferroptosis and partially restores Hippo pathway activity.\",\n      \"method\": \"PLIN4 knockdown/overexpression by vector transfection in HT22 cells; RT-qPCR, immunostaining, western blot for Hippo pathway components; transmission electron microscopy; Fe2+ measurement\",\n      \"journal\": \"Neurotoxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — KD with pathway placement but mechanistic link between PLIN4 and Hippo pathway is correlative, single lab\",\n      \"pmids\": [\"39182851\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLIN4 is a PPARγ-regulated amphipathic helix protein that coats nascent lipid droplets in adipocytes and other cell types, where its lipid droplet localization is controlled post-translationally by SENP7-mediated deSUMOylation; at the organismal level it regulates cardiac lipid storage partly by controlling Plin5 expression, and in neurons excess PLIN4-dependent lipid droplet accumulation inhibits mitophagy via the parkin-p62 axis and promotes ferroptosis, while SH2B1 counteracts this by recruiting HSC70 to drive lysosomal degradation of PLIN4; repeat expansion in PLIN4 causes autosomal dominant vacuolar myopathy, mechanistically linked to accelerated amyloid fibril formation by the repetitive amphipathic helix domain.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PLIN4 is a PPARγ-regulated lipid droplet coat protein whose tandem 33-amino-acid amphipathic helix repeats enable rapid, reversible association with nascent triacylglycerol-rich lipid droplets in adipocytes and other cell types [PMID:12840023, PMID:15111493]. Its lipid droplet targeting is controlled post-translationally by SENP7-mediated deSUMOylation, and in the cytosol PLIN4 is turned over via HSC70-dependent lysosomal degradation promoted by SH2B1 [PMID:38677512, PMID:35390677]. At the organismal level, Plin4 deficiency reduces cardiac and hepatic triacylglycerol storage—partly by downregulating Plin5 in the heart—and modulates ER stress and adipose inflammation under dietary stress, while excess PLIN4-dependent lipid droplet accumulation in neurons inhibits parkin–p62-mediated mitophagy and promotes ferroptosis [PMID:23423172, PMID:41391763, PMID:29967574, PMID:39173539]. The ~1000-amino-acid repetitive amphipathic helix domain can form amyloid fibrils in vitro, and repeat expansion linked to autosomal dominant vacuolar myopathy accelerates this fibrillation, with lipid droplet binding and amyloid self-assembly representing competing fates for the protein [PMID:12840023].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that PLIN4 is a lipid droplet coat protein resolved its subcellular function: it redistributes from the cytoplasm to nascent peripheral lipid droplets upon fatty acid loading, in a triacylglycerol synthesis–dependent manner.\",\n      \"evidence\": \"Immunofluorescence of oleate-treated 3T3-L1 adipocytes with triacylglycerol synthesis inhibitor\",\n      \"pmids\": [\"12840023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which PLIN4 selectively targets nascent versus mature lipid droplets was not defined\",\n        \"Structural basis of the amphipathic helix–lipid droplet interaction not resolved\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying PLIN4 as a direct PPARγ transcriptional target explained its adipose-enriched expression and linked it to the master adipogenic program.\",\n      \"evidence\": \"Promoter-reporter assays identifying three conserved PPREs; expression analysis in adipocytes and Zucker rats\",\n      \"pmids\": [\"15111493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional transcription factors cooperate with PPARγ at the PLIN4 locus was not tested\",\n        \"Regulation in non-adipose tissues not addressed\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that PLIN4 belongs to a pre-existing cytosolic reservoir of coat proteins (with adipophilin and TIP47) that package triacylglycerol without new protein synthesis established a rapid-response lipid storage mechanism.\",\n      \"evidence\": \"Subcellular fractionation and cycloheximide treatment of oleate-loaded 3T3-L1 adipocytes\",\n      \"pmids\": [\"15731108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional redundancy or hierarchy among the three coat proteins was not resolved\",\n        \"Post-translational signals controlling redistribution were unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The Plin4 knockout mouse revealed an unexpected tissue-specific role in the heart: Plin4 loss reduced cardiac triacylglycerol and dramatically decreased Plin5 expression, linking PLIN4 to cardiac lipid homeostasis beyond a simple coat function.\",\n      \"evidence\": \"Gene-targeted Plin4−/− mice subjected to fasting, high-fat diet, and leptin-deficiency challenges with cardiac lipid quantification and qPCR\",\n      \"pmids\": [\"23423172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which Plin4 controls Plin5 transcription in the heart is unknown\",\n        \"Whether cardiac protection from steatosis translates to functional cardiac benefit was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placing PLIN4-dependent lipid droplet accumulation upstream of impaired parkin–ubiquitin–p62 mitophagy in dopaminergic neurons provided a mechanistic link between lipid storage and neurodegeneration in a Parkinson's disease model.\",\n      \"evidence\": \"Plin4 siRNA in SH-SY5Y cells and primary neurons; MPTP/p mouse model with TH-neuron quantification\",\n      \"pmids\": [\"29967574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PLIN4-coated lipid droplets physically sequester parkin or p62 was not shown\",\n        \"Not independently replicated\",\n        \"Causal direction between lipid droplet excess and mitophagy inhibition not fully dissected\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that PLIN4 is required for lipid droplet stability and viability in chemoresistant triple-negative breast cancer cells extended its functional significance to cancer biology.\",\n      \"evidence\": \"PLIN4 siRNA in MDA-MB-436 chemoresistant cells with lipid droplet imaging and viability assays\",\n      \"pmids\": [\"31537618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic basis of chemoresistance dependence on PLIN4-coated lipid droplets was not elucidated\",\n        \"Limited to a single cell line\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying SH2B1 as a recruiter of HSC70 that drives lysosomal degradation of PLIN4 defined a post-translational clearance pathway and explained how PLIN4 protein levels are constrained to prevent lipid peroxidation and neuronal apoptosis.\",\n      \"evidence\": \"Co-IP of SH2B1–HSC70; Sh2b1 KO and neuron-specific overexpression in MPTP mice; AAV-HSC70 rescue\",\n      \"pmids\": [\"35390677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct ubiquitin or chaperone-mediated autophagy signals on PLIN4 were not mapped\",\n        \"Whether this degradation pathway operates in non-neuronal tissues is untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that SENP7-mediated deSUMOylation is required for PLIN4 lipid droplet targeting resolved a key post-translational switch: SUMOylated PLIN4 fails to coat droplets, resulting in smaller droplets and reduced adipose mass.\",\n      \"evidence\": \"Conventional and adipocyte-specific Senp7 KO mice; biochemical deSUMOylation assay\",\n      \"pmids\": [\"38677512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific SUMO-modified residues on PLIN4 were not identified\",\n        \"Whether SUMOylation affects PLIN4 stability or only localization is unclear\",\n        \"Not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that PLIN4 upregulation promotes ferroptosis in Leydig cells (via cadmium/m6A pathway) and hippocampal neurons (via sevoflurane) broadened PLIN4's pathological roles to iron-dependent cell death across tissues.\",\n      \"evidence\": \"Plin4 siRNA in Leydig cells with Fe²⁺ and lipid droplet quantification; PLIN4 KD/OE in HT22 hippocampal cells with ferroptosis markers\",\n      \"pmids\": [\"39173539\", \"39182851\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanism linking PLIN4/lipid droplets to lipid peroxidation and iron metabolism is not defined\",\n        \"Hippo pathway connection (PMID:39182851) is correlative with low confidence\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Plin4 knockout in diet-obese female mice revealed a hepatoprotective role: Plin4 loss reduced hepatic triacylglycerol and PERK-dependent ER stress, but increased adipose inflammation, suggesting tissue-opposing metabolic functions.\",\n      \"evidence\": \"Plin4−/− mice on Western diet; hepatic lipid quantification, ER stress markers, adipose histology\",\n      \"pmids\": [\"41391763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Link between PLIN4 and PERK pathway is correlative\",\n        \"Mechanism of increased adipose inflammation in the absence of Plin4 is unknown\",\n        \"Sex-specific effects not tested in males\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Structural demonstration that the PLIN4 tandem 33-aa amphipathic helix repeat domain forms amyloid fibrils—accelerated by disease-associated repeat expansion—and that lipid droplet binding competes with fibrillation provided a molecular mechanism for PLIN4 repeat-expansion vacuolar myopathy.\",\n      \"evidence\": \"(preprint) Cryo-EM, atomic force microscopy of purified repeat fragments; fibrillation kinetics; cell-based lipid droplet binding competition assay\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Not yet peer-reviewed\",\n        \"In vivo fibril formation in patient muscle not demonstrated\",\n        \"Repeat expansion threshold for clinical disease not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise structural basis by which PLIN4 amphipathic helices coat lipid droplet monolayers, the SUMO acceptor sites controlling its localization, the mechanism linking PLIN4-coated droplets to ferroptosis and mitophagy inhibition, and the in vivo relevance of amyloid fibril formation in myopathy remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of PLIN4 on a lipid droplet surface\",\n        \"SUMO modification sites unmapped\",\n        \"Causal mechanism connecting lipid droplet coating to iron-dependent cell death not established\",\n        \"Patient tissue confirmation of amyloid fibrils absent\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [0, 1, 6, 9, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 3, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SENP7\",\n      \"SH2B1\",\n      \"HSPA8\",\n      \"PLIN5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}