{"gene":"PLIN4","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"S3-12 (PLIN4) coats nascent lipid droplets in adipocytes in response to fatty acid loading; it localizes initially to ~500-nm peripheral structures and then to larger lipid droplet surfaces, in a process requiring glucose, fatty acids incorporable into triacylglycerol, and insulin, and blocked by a triacylglycerol synthesis inhibitor.","method":"Immunofluorescence microscopy of 3T3-L1 adipocytes; pharmacological inhibition of TAG synthesis; insulin withdrawal","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct imaging with multiple orthogonal pharmacological conditions in a focused, well-controlled study replicated by the same group","pmids":["12840023"],"is_preprint":false},{"year":2005,"finding":"S3-12 (PLIN4), together with TIP47 and adipophilin, forms the initial coat of nascent lipid droplets emerging upon oleate loading of adipocytes; after 100 min, S3-12 and TIP47 coat smaller peripheral droplets while adipophilin coats a more medial population. This coat assembly is independent of new protein synthesis (cycloheximide-insensitive), indicating a pre-existing cytosolic reservoir of S3-12 is recruited to newly forming droplets.","method":"Immunofluorescence microscopy, cell fractionation (lipid droplet vs. cytosol fractions), cycloheximide inhibition of protein synthesis in 3T3-L1 adipocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, fractionation, cycloheximide block), replication of earlier findings with extended mechanistic detail","pmids":["15731108"],"is_preprint":false},{"year":2004,"finding":"S3-12 (PLIN4) is a direct transcriptional target of PPARγ; the S3-12 promoter contains three evolutionarily conserved PPAR response elements (PPREs) that mediate PPARγ-dependent transactivation, establishing PPARγ as the upstream transcriptional regulator of PLIN4 expression in adipose tissue.","method":"Promoter characterization (reporter assays, PPRE identification), gene expression analysis in adipocytes and Zucker rat adipose tissue","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assays plus in vivo expression data, single lab","pmids":["15111493"],"is_preprint":false},{"year":2013,"finding":"Genetic inactivation of Plin4 in mice reduces Plin5 protein (by ~87%) and mRNA (~38%) specifically in the heart, and markedly reduces cardiac triacylglycerol content under normal diet, prolonged fasting, high-fat diet, and leptin-deficient obesity, without affecting other metabolic genes or heart function; Plin4 loss does not affect body composition, adipose mass, or TAG in other oxidative tissues.","method":"Gene-targeted Plin4-/- mice; qRT-PCR, western blot, lipid extraction/TAG quantification, echocardiography","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple tissue/metabolic phenotypic readouts across several dietary challenges, replicated across conditions","pmids":["23423172"],"is_preprint":false},{"year":2018,"finding":"In an MPTP/p mouse model of Parkinson's disease, Plin4 is upregulated in dopaminergic neurons, and Plin4-dependent lipid droplet accumulation inhibits mitophagy via the parkin–poly-Ub–p62 pathway, leading to mitochondrial damage and neuronal death; siRNA-mediated Plin4 knockdown restores autophagy flux and promotes neuronal survival.","method":"In vivo MPTP/p mouse model; in vitro SH-SY5Y and primary dopaminergic neuron cultures; Plin4 siRNA knockdown; autophagy flux assays; assessment of parkin/p62 pathway","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro models with pathway dissection, single lab, mechanistic follow-up with autophagy inhibitor rescue experiment","pmids":["29967574"],"is_preprint":false},{"year":2022,"finding":"SH2B1 promotes HSC70-mediated recognition and lysosomal translocation and degradation of PLIN4 in neurons; this SH2B1–HSC70–PLIN4 axis suppresses lipid peroxidation and neuronal apoptosis in MPTP-treated PD mice. SH2B1 binds HSC70 (co-immunoprecipitation), and AAV-mediated HSC70 rescue is sufficient in wild-type but not Sh2b1-deficient mice.","method":"Co-immunoprecipitation (SH2B1–HSC70 interaction), Sh2b1 KO and neuron-specific overexpression mice, AAV rescue, SH-SY5Y cell knockdown/overexpression, western blot, lipid peroxidation assays","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo genetic rescue experiments, single lab, multiple orthogonal approaches","pmids":["35390677"],"is_preprint":false},{"year":2024,"finding":"SENP7 deSUMOylates PLIN4 in white adipocytes, and this deSUMOylation promotes PLIN4 localization to lipid droplets; Senp7-deficient mice display reduced white adipose tissue mass, smaller adipocytes, and smaller lipid droplets, phenocopying impaired lipid droplet maturation.","method":"Conventional and adipocyte-specific Senp7 KO mice; lipid droplet morphology analysis; mechanistic deSUMOylation assays linking Senp7 to Plin4 SUMOylation status and LD localization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with cellular phenotype plus direct biochemical deSUMOylation mechanism, single lab","pmids":["38677512"],"is_preprint":false},{"year":2024,"finding":"In testicular Leydig cells, environmental stress (cadmium) increases PLIN4 via METTL3/METTL14 m6A methylation-dependent upregulation; elevated PLIN4 promotes lipid droplet deposition and ferroptosis, reducing testosterone; Plin4 siRNA reverses lipid droplet accumulation and ferroptosis. Inhibition of METTL3/METTL14 with S-adenosylhomocysteine restores Plin4 and testosterone levels.","method":"In vivo cadmium-exposed rodent model; in vitro Leydig cell siRNA knockdown; ferroptosis inhibitor (ferrostatin-1) rescue; METTL3/METTL14 inhibitor experiments; Fe2+, testosterone, and lipid droplet quantification","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro models with siRNA, pharmacological rescue, and upstream m6A mechanism identification, single lab","pmids":["39173539"],"is_preprint":false},{"year":2025,"finding":"Plin4 deficiency in diet-obese mice fed a Western diet reduces hepatic triacylglyceride levels and expression of PERK-downstream ER stress markers in the liver, and elevates adipose macrophage markers/crown-like structures in ovarian WAT, without affecting adipocyte size; lean Plin4-/- mice show altered Plin5 expression in heart, liver, and WAT.","method":"Plin4-/- mice on Western diet; lipid extraction/quantification, ER stress marker expression (western blot/qPCR), histology (crown-like structures, adipocyte size), metabolic phenotyping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with tissue-specific phenotypic readouts, single lab, multiple endpoints","pmids":["41391763"],"is_preprint":false},{"year":2025,"finding":"The repetitive region of PLIN4 (tandem 33-aa amphipathic helix repeats, ~1000 aa) forms amyloid fibrils in vitro; repeat expansion accelerates fibril formation. The presence of lipid droplets attenuates PLIN4 aggregation, indicating that lipid binding competes with self-assembly. The repeat expansion does not significantly alter PLIN4 interaction with lipid droplets in cells.","method":"Cryo-EM and atomic force microscopy of purified PLIN4 repeat fragments; cell-based lipid droplet interaction assays with expanded vs. normal repeat constructs","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — cryo-EM structural characterization plus cell-based assays, single lab, preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"PLIN4 (S3-12) is a PPARγ-regulated lipid droplet coat protein of the perilipin family that is recruited from a pre-existing cytosolic pool to coat nascent triacylglycerol-filled lipid droplets in adipocytes; its localization to lipid droplets is promoted by SENP7-mediated deSUMOylation, and its stability is regulated by HSC70-dependent lysosomal degradation facilitated by SH2B1; in the heart, PLIN4 controls Plin5 levels and cardiac lipid accumulation; in neurons, excessive PLIN4-dependent lipid droplet accumulation inhibits mitophagy via the parkin–p62 pathway and promotes ferroptosis; its unusually long amphipathic repeat region can form amyloid fibrils in vitro, with repeat expansion accelerating aggregation—a property linked to a dominantly inherited vacuolar myopathy."},"narrative":{"mechanistic_narrative":"PLIN4 (S3-12) is a perilipin-family lipid droplet coat protein that is recruited from a pre-existing cytosolic reservoir to coat nascent triacylglycerol-filled lipid droplets emerging upon fatty acid loading in adipocytes, acting at the earliest, smallest peripheral droplets in concert with TIP47 and adipophilin [PMID:12840023, PMID:15731108]. Its expression is driven transcriptionally by PPARγ acting through conserved PPAR response elements in the PLIN4 promoter [PMID:15111493]. Recruitment to the droplet surface is controlled post-translationally: SENP7-mediated deSUMOylation promotes PLIN4 localization to lipid droplets and is required for normal adipocyte lipid droplet maturation [PMID:38677512], while PLIN4 protein stability is set by SH2B1-assisted, HSC70-mediated lysosomal degradation [PMID:35390677]. PLIN4 governs tissue lipid storage in vivo — its loss reduces cardiac and hepatic triacylglyceride content and lowers Plin5 levels across heart, liver, and adipose tissue, while perturbing ER stress and adipose inflammatory phenotypes [PMID:23423172, PMID:41391763]. Beyond storage, excessive PLIN4-dependent lipid droplet accumulation is pathogenic: in dopaminergic neurons it inhibits mitophagy via the parkin–p62 pathway driving neuronal death [PMID:29967574], and in Leydig cells METTL3/METTL14 m6A-dependent PLIN4 upregulation drives lipid droplet deposition and ferroptosis [PMID:39173539]. The protein's unusually long amphipathic tandem-repeat region can self-assemble into amyloid fibrils in vitro, with repeat expansion accelerating aggregation and lipid droplet binding competing with fibril formation.","teleology":[{"year":2003,"claim":"Established that PLIN4 is a coat protein for newly forming lipid droplets, defining its core cellular role as droplet-surface association coupled to active triacylglycerol synthesis.","evidence":"Immunofluorescence of 3T3-L1 adipocytes under fatty acid loading with pharmacological TAG-synthesis inhibition and insulin withdrawal","pmids":["12840023"],"confidence":"High","gaps":["Did not define the targeting motif on PLIN4 that mediates droplet binding","Mechanism linking insulin signaling to recruitment not resolved"]},{"year":2004,"claim":"Identified the upstream transcriptional control of PLIN4, placing it downstream of PPARγ in the adipogenic program.","evidence":"Promoter reporter assays with PPRE mapping plus adipose expression analysis in Zucker rats","pmids":["15111493"],"confidence":"Medium","gaps":["Single-lab promoter analysis","Does not address post-transcriptional regulation of PLIN4"]},{"year":2005,"claim":"Resolved how PLIN4 reaches nascent droplets, showing recruitment from a pre-existing cytosolic pool rather than new synthesis, and ordering it with TIP47/adipophilin on distinct droplet subpopulations.","evidence":"Immunofluorescence, lipid droplet/cytosol fractionation, and cycloheximide block in 3T3-L1 adipocytes","pmids":["15731108"],"confidence":"High","gaps":["Molecular signal triggering cytosol-to-droplet recruitment not identified","Functional consequence of the peripheral vs. medial droplet segregation unknown"]},{"year":2013,"claim":"Demonstrated in vivo physiological function via genetic loss, revealing PLIN4 as a tissue-specific regulator of cardiac lipid storage and Plin5 abundance.","evidence":"Plin4-/- mice with TAG quantification, qRT-PCR/western blot, and echocardiography across dietary challenges","pmids":["23423172"],"confidence":"High","gaps":["Mechanism by which PLIN4 controls Plin5 protein levels unresolved","Tissue specificity of the cardiac phenotype unexplained"]},{"year":2018,"claim":"Extended PLIN4 function to neurodegeneration, linking PLIN4-driven lipid droplet accumulation to mitophagy suppression and dopaminergic neuron death.","evidence":"MPTP/p mouse model, SH-SY5Y and primary neuron cultures, Plin4 siRNA, and autophagy flux/parkin-p62 pathway assays","pmids":["29967574"],"confidence":"Medium","gaps":["How lipid droplets mechanistically block the parkin-p62 axis not defined","Single-lab model system"]},{"year":2022,"claim":"Identified the degradation arm of PLIN4 regulation, establishing an SH2B1–HSC70 chaperone-mediated lysosomal pathway that limits PLIN4 and protects neurons.","evidence":"Co-IP of SH2B1–HSC70, Sh2b1 KO and overexpression mice, AAV rescue, and lipid peroxidation assays","pmids":["35390677"],"confidence":"Medium","gaps":["Direct PLIN4–HSC70 binding interface not mapped","Whether SH2B1 binds PLIN4 directly versus via HSC70 unresolved"]},{"year":2024,"claim":"Revealed deSUMOylation as the post-translational switch controlling PLIN4 droplet localization, connecting SENP7 to adipocyte lipid droplet maturation.","evidence":"Conventional and adipocyte-specific Senp7 KO mice with droplet morphology and deSUMOylation assays","pmids":["38677512"],"confidence":"Medium","gaps":["SUMOylation site(s) on PLIN4 not specified","How SUMO status alters droplet affinity mechanistically unknown"]},{"year":2024,"claim":"Linked epitranscriptomic upregulation of PLIN4 to ferroptosis, showing m6A-dependent induction drives lipid droplet deposition and reproductive toxicity.","evidence":"Cadmium-exposed rodents, Leydig cell siRNA, ferrostatin-1 and METTL3/METTL14 inhibitor rescue","pmids":["39173539"],"confidence":"Medium","gaps":["Direct m6A sites on PLIN4 transcript not mapped","Causal chain from lipid droplets to ferroptotic lipid peroxidation incompletely defined"]},{"year":2025,"claim":"Broadened the in vivo metabolic role of PLIN4 loss to hepatic lipid storage and ER stress, refining its cross-tissue regulation of Plin5.","evidence":"Plin4-/- mice on Western diet with hepatic TAG, PERK ER stress markers, and adipose histology","pmids":["41391763"],"confidence":"Medium","gaps":["Mechanistic link between PLIN4 and PERK ER stress signaling unresolved","Cause of adipose inflammatory phenotype not established"]},{"year":2025,"claim":"Characterized the biophysical behavior of the PLIN4 amphipathic repeat region, showing it forms amyloid fibrils with repeat expansion accelerating aggregation and lipid binding competing with self-assembly.","evidence":"Cryo-EM and AFM of purified repeat fragments plus cell-based lipid droplet interaction assays (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","In vivo relevance of fibril formation to disease not demonstrated in this corpus","Cellular trigger for aggregation versus droplet binding unknown"]},{"year":null,"claim":"How the multiple post-translational controls (SUMOylation, chaperone-mediated degradation), transcriptional/m6A inputs, and the amyloidogenic repeat region are integrated to determine PLIN4 droplet residence, stability, and pathogenic aggregation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting droplet binding to fibril propensity in cells","Structural basis of droplet targeting not defined","Link between biophysical aggregation and the vacuolar myopathy phenotype not established in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,8]},{"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":["HSC70","SH2B1","SENP7","PPARG"],"other_free_text":[]}},"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":292,"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":192,"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":184,"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":94,"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":74,"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":30,"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":23,"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":19,"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":13,"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":"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":7,"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":"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":2,"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 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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":11678,"output_tokens":2874,"usd":0.039072,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10246,"output_tokens":3502,"usd":0.06939,"stage2_stop_reason":"end_turn"},"total_usd":0.108462,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"S3-12 (PLIN4) coats nascent lipid droplets in adipocytes in response to fatty acid loading; it localizes initially to ~500-nm peripheral structures and then to larger lipid droplet surfaces, in a process requiring glucose, fatty acids incorporable into triacylglycerol, and insulin, and blocked by a triacylglycerol synthesis inhibitor.\",\n      \"method\": \"Immunofluorescence microscopy of 3T3-L1 adipocytes; pharmacological inhibition of TAG synthesis; insulin withdrawal\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct imaging with multiple orthogonal pharmacological conditions in a focused, well-controlled study replicated by the same group\",\n      \"pmids\": [\"12840023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"S3-12 (PLIN4), together with TIP47 and adipophilin, forms the initial coat of nascent lipid droplets emerging upon oleate loading of adipocytes; after 100 min, S3-12 and TIP47 coat smaller peripheral droplets while adipophilin coats a more medial population. This coat assembly is independent of new protein synthesis (cycloheximide-insensitive), indicating a pre-existing cytosolic reservoir of S3-12 is recruited to newly forming droplets.\",\n      \"method\": \"Immunofluorescence microscopy, cell fractionation (lipid droplet vs. cytosol fractions), cycloheximide inhibition of protein synthesis in 3T3-L1 adipocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, fractionation, cycloheximide block), replication of earlier findings with extended mechanistic detail\",\n      \"pmids\": [\"15731108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"S3-12 (PLIN4) is a direct transcriptional target of PPARγ; the S3-12 promoter contains three evolutionarily conserved PPAR response elements (PPREs) that mediate PPARγ-dependent transactivation, establishing PPARγ as the upstream transcriptional regulator of PLIN4 expression in adipose tissue.\",\n      \"method\": \"Promoter characterization (reporter assays, PPRE identification), gene expression analysis in adipocytes and Zucker rat adipose tissue\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assays plus in vivo expression data, single lab\",\n      \"pmids\": [\"15111493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Genetic inactivation of Plin4 in mice reduces Plin5 protein (by ~87%) and mRNA (~38%) specifically in the heart, and markedly reduces cardiac triacylglycerol content under normal diet, prolonged fasting, high-fat diet, and leptin-deficient obesity, without affecting other metabolic genes or heart function; Plin4 loss does not affect body composition, adipose mass, or TAG in other oxidative tissues.\",\n      \"method\": \"Gene-targeted Plin4-/- mice; qRT-PCR, western blot, lipid extraction/TAG quantification, echocardiography\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple tissue/metabolic phenotypic readouts across several dietary challenges, replicated across conditions\",\n      \"pmids\": [\"23423172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In an MPTP/p mouse model of Parkinson's disease, Plin4 is upregulated in dopaminergic neurons, and Plin4-dependent lipid droplet accumulation inhibits mitophagy via the parkin–poly-Ub–p62 pathway, leading to mitochondrial damage and neuronal death; siRNA-mediated Plin4 knockdown restores autophagy flux and promotes neuronal survival.\",\n      \"method\": \"In vivo MPTP/p mouse model; in vitro SH-SY5Y and primary dopaminergic neuron cultures; Plin4 siRNA knockdown; autophagy flux assays; assessment of parkin/p62 pathway\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro models with pathway dissection, single lab, mechanistic follow-up with autophagy inhibitor rescue experiment\",\n      \"pmids\": [\"29967574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SH2B1 promotes HSC70-mediated recognition and lysosomal translocation and degradation of PLIN4 in neurons; this SH2B1–HSC70–PLIN4 axis suppresses lipid peroxidation and neuronal apoptosis in MPTP-treated PD mice. SH2B1 binds HSC70 (co-immunoprecipitation), and AAV-mediated HSC70 rescue is sufficient in wild-type but not Sh2b1-deficient mice.\",\n      \"method\": \"Co-immunoprecipitation (SH2B1–HSC70 interaction), Sh2b1 KO and neuron-specific overexpression mice, AAV rescue, SH-SY5Y cell knockdown/overexpression, western blot, lipid peroxidation assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo genetic rescue experiments, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"35390677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP7 deSUMOylates PLIN4 in white adipocytes, and this deSUMOylation promotes PLIN4 localization to lipid droplets; Senp7-deficient mice display reduced white adipose tissue mass, smaller adipocytes, and smaller lipid droplets, phenocopying impaired lipid droplet maturation.\",\n      \"method\": \"Conventional and adipocyte-specific Senp7 KO mice; lipid droplet morphology analysis; mechanistic deSUMOylation assays linking Senp7 to Plin4 SUMOylation status and LD localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with cellular phenotype plus direct biochemical deSUMOylation mechanism, single lab\",\n      \"pmids\": [\"38677512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In testicular Leydig cells, environmental stress (cadmium) increases PLIN4 via METTL3/METTL14 m6A methylation-dependent upregulation; elevated PLIN4 promotes lipid droplet deposition and ferroptosis, reducing testosterone; Plin4 siRNA reverses lipid droplet accumulation and ferroptosis. Inhibition of METTL3/METTL14 with S-adenosylhomocysteine restores Plin4 and testosterone levels.\",\n      \"method\": \"In vivo cadmium-exposed rodent model; in vitro Leydig cell siRNA knockdown; ferroptosis inhibitor (ferrostatin-1) rescue; METTL3/METTL14 inhibitor experiments; Fe2+, testosterone, and lipid droplet quantification\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro models with siRNA, pharmacological rescue, and upstream m6A mechanism identification, single lab\",\n      \"pmids\": [\"39173539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Plin4 deficiency in diet-obese mice fed a Western diet reduces hepatic triacylglyceride levels and expression of PERK-downstream ER stress markers in the liver, and elevates adipose macrophage markers/crown-like structures in ovarian WAT, without affecting adipocyte size; lean Plin4-/- mice show altered Plin5 expression in heart, liver, and WAT.\",\n      \"method\": \"Plin4-/- mice on Western diet; lipid extraction/quantification, ER stress marker expression (western blot/qPCR), histology (crown-like structures, adipocyte size), metabolic phenotyping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with tissue-specific phenotypic readouts, single lab, multiple endpoints\",\n      \"pmids\": [\"41391763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The repetitive region of PLIN4 (tandem 33-aa amphipathic helix repeats, ~1000 aa) forms amyloid fibrils in vitro; repeat expansion accelerates fibril formation. The presence of lipid droplets attenuates PLIN4 aggregation, indicating that lipid binding competes with self-assembly. The repeat expansion does not significantly alter PLIN4 interaction with lipid droplets in cells.\",\n      \"method\": \"Cryo-EM and atomic force microscopy of purified PLIN4 repeat fragments; cell-based lipid droplet interaction assays with expanded vs. normal repeat constructs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — cryo-EM structural characterization plus cell-based assays, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PLIN4 (S3-12) is a PPARγ-regulated lipid droplet coat protein of the perilipin family that is recruited from a pre-existing cytosolic pool to coat nascent triacylglycerol-filled lipid droplets in adipocytes; its localization to lipid droplets is promoted by SENP7-mediated deSUMOylation, and its stability is regulated by HSC70-dependent lysosomal degradation facilitated by SH2B1; in the heart, PLIN4 controls Plin5 levels and cardiac lipid accumulation; in neurons, excessive PLIN4-dependent lipid droplet accumulation inhibits mitophagy via the parkin–p62 pathway and promotes ferroptosis; its unusually long amphipathic repeat region can form amyloid fibrils in vitro, with repeat expansion accelerating aggregation—a property linked to a dominantly inherited vacuolar myopathy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLIN4 (S3-12) is a perilipin-family lipid droplet coat protein that is recruited from a pre-existing cytosolic reservoir to coat nascent triacylglycerol-filled lipid droplets emerging upon fatty acid loading in adipocytes, acting at the earliest, smallest peripheral droplets in concert with TIP47 and adipophilin [#0, #1]. Its expression is driven transcriptionally by PPARγ acting through conserved PPAR response elements in the PLIN4 promoter [#2]. Recruitment to the droplet surface is controlled post-translationally: SENP7-mediated deSUMOylation promotes PLIN4 localization to lipid droplets and is required for normal adipocyte lipid droplet maturation [#6], while PLIN4 protein stability is set by SH2B1-assisted, HSC70-mediated lysosomal degradation [#5]. PLIN4 governs tissue lipid storage in vivo — its loss reduces cardiac and hepatic triacylglyceride content and lowers Plin5 levels across heart, liver, and adipose tissue, while perturbing ER stress and adipose inflammatory phenotypes [#3, #8]. Beyond storage, excessive PLIN4-dependent lipid droplet accumulation is pathogenic: in dopaminergic neurons it inhibits mitophagy via the parkin–p62 pathway driving neuronal death [#4], and in Leydig cells METTL3/METTL14 m6A-dependent PLIN4 upregulation drives lipid droplet deposition and ferroptosis [#7]. The protein's unusually long amphipathic tandem-repeat region can self-assemble into amyloid fibrils in vitro, with repeat expansion accelerating aggregation and lipid droplet binding competing with fibril formation [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that PLIN4 is a coat protein for newly forming lipid droplets, defining its core cellular role as droplet-surface association coupled to active triacylglycerol synthesis.\",\n      \"evidence\": \"Immunofluorescence of 3T3-L1 adipocytes under fatty acid loading with pharmacological TAG-synthesis inhibition and insulin withdrawal\",\n      \"pmids\": [\"12840023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the targeting motif on PLIN4 that mediates droplet binding\", \"Mechanism linking insulin signaling to recruitment not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the upstream transcriptional control of PLIN4, placing it downstream of PPARγ in the adipogenic program.\",\n      \"evidence\": \"Promoter reporter assays with PPRE mapping plus adipose expression analysis in Zucker rats\",\n      \"pmids\": [\"15111493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab promoter analysis\", \"Does not address post-transcriptional regulation of PLIN4\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved how PLIN4 reaches nascent droplets, showing recruitment from a pre-existing cytosolic pool rather than new synthesis, and ordering it with TIP47/adipophilin on distinct droplet subpopulations.\",\n      \"evidence\": \"Immunofluorescence, lipid droplet/cytosol fractionation, and cycloheximide block in 3T3-L1 adipocytes\",\n      \"pmids\": [\"15731108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signal triggering cytosol-to-droplet recruitment not identified\", \"Functional consequence of the peripheral vs. medial droplet segregation unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated in vivo physiological function via genetic loss, revealing PLIN4 as a tissue-specific regulator of cardiac lipid storage and Plin5 abundance.\",\n      \"evidence\": \"Plin4-/- mice with TAG quantification, qRT-PCR/western blot, and echocardiography across dietary challenges\",\n      \"pmids\": [\"23423172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PLIN4 controls Plin5 protein levels unresolved\", \"Tissue specificity of the cardiac phenotype unexplained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended PLIN4 function to neurodegeneration, linking PLIN4-driven lipid droplet accumulation to mitophagy suppression and dopaminergic neuron death.\",\n      \"evidence\": \"MPTP/p mouse model, SH-SY5Y and primary neuron cultures, Plin4 siRNA, and autophagy flux/parkin-p62 pathway assays\",\n      \"pmids\": [\"29967574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How lipid droplets mechanistically block the parkin-p62 axis not defined\", \"Single-lab model system\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the degradation arm of PLIN4 regulation, establishing an SH2B1–HSC70 chaperone-mediated lysosomal pathway that limits PLIN4 and protects neurons.\",\n      \"evidence\": \"Co-IP of SH2B1–HSC70, Sh2b1 KO and overexpression mice, AAV rescue, and lipid peroxidation assays\",\n      \"pmids\": [\"35390677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PLIN4–HSC70 binding interface not mapped\", \"Whether SH2B1 binds PLIN4 directly versus via HSC70 unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed deSUMOylation as the post-translational switch controlling PLIN4 droplet localization, connecting SENP7 to adipocyte lipid droplet maturation.\",\n      \"evidence\": \"Conventional and adipocyte-specific Senp7 KO mice with droplet morphology and deSUMOylation assays\",\n      \"pmids\": [\"38677512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMOylation site(s) on PLIN4 not specified\", \"How SUMO status alters droplet affinity mechanistically unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked epitranscriptomic upregulation of PLIN4 to ferroptosis, showing m6A-dependent induction drives lipid droplet deposition and reproductive toxicity.\",\n      \"evidence\": \"Cadmium-exposed rodents, Leydig cell siRNA, ferrostatin-1 and METTL3/METTL14 inhibitor rescue\",\n      \"pmids\": [\"39173539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct m6A sites on PLIN4 transcript not mapped\", \"Causal chain from lipid droplets to ferroptotic lipid peroxidation incompletely defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the in vivo metabolic role of PLIN4 loss to hepatic lipid storage and ER stress, refining its cross-tissue regulation of Plin5.\",\n      \"evidence\": \"Plin4-/- mice on Western diet with hepatic TAG, PERK ER stress markers, and adipose histology\",\n      \"pmids\": [\"41391763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between PLIN4 and PERK ER stress signaling unresolved\", \"Cause of adipose inflammatory phenotype not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Characterized the biophysical behavior of the PLIN4 amphipathic repeat region, showing it forms amyloid fibrils with repeat expansion accelerating aggregation and lipid binding competing with self-assembly.\",\n      \"evidence\": \"Cryo-EM and AFM of purified repeat fragments plus cell-based lipid droplet interaction assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"In vivo relevance of fibril formation to disease not demonstrated in this corpus\", \"Cellular trigger for aggregation versus droplet binding unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple post-translational controls (SUMOylation, chaperone-mediated degradation), transcriptional/m6A inputs, and the amyloidogenic repeat region are integrated to determine PLIN4 droplet residence, stability, and pathogenic aggregation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model connecting droplet binding to fibril propensity in cells\", \"Structural basis of droplet targeting not defined\", \"Link between biophysical aggregation and the vacuolar myopathy phenotype not established in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 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\": [\"HSC70\", \"SH2B1\", \"SENP7\", \"PPARG\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}