{"gene":"PLIN5","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2006,"finding":"PLIN5 (OXPAT/MLDP/LSDP5) localizes to the surface of lipid droplets in oxidative tissues and co-localizes with adipophilin (ADRP) on lipid droplets in primary cardiomyocytes. Ectopic expression promotes fatty acid-induced triacylglycerol accumulation and long-chain fatty acid oxidation.","method":"Subcellular fractionation, immunofluorescence co-localization in primary cardiomyocytes, ectopic overexpression with metabolic flux assays","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fractionation and imaging, functional consequence shown by overexpression with metabolic readouts, single lab","pmids":["17130488"],"is_preprint":false},{"year":2006,"finding":"PLIN5 (LSDP5) associates with lipid storage droplets when ectopically expressed as YFP or FLAG fusion proteins, and forced expression in CHO cells inhibits lipolysis of intracellular lipid droplets.","method":"Fluorescent fusion protein expression, lipid droplet fractionation, lipolysis assay in CHO cells","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (lipolysis inhibition), single lab, two orthogonal methods","pmids":["17234449"],"is_preprint":false},{"year":2006,"finding":"PLIN5 (MLDP) is enriched on lipid droplet surfaces in the heart; the N-terminal PAT-1 domain plus the adjacent 33-mer domain are required for lipid droplet targeting. Expression is regulated by PPARalpha and induced by fasting.","method":"GFP fusion protein overexpression, deletion analysis, subcellular fractionation, PPARalpha knockout mice","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping via deletion mutants with direct localization readout, single lab, multiple orthogonal methods","pmids":["16571721"],"is_preprint":false},{"year":2008,"finding":"PLIN5 (Mldp) binds ABHD5 (CGI-58, the co-activator of ATGL) on the surface of lipid droplets in cardiac muscle fibers. This interaction is dynamic, enhanced by oleic acid treatment in a triglyceride-synthesis-dependent manner, and essential for ATGL activity at PLIN5-containing lipid droplets; an ABHD5 mutant (E262K) that cannot bind PLIN5 fails to prevent lipid droplet accumulation in cells expressing PLIN5.","method":"Protein interaction assays in transfected fibroblasts, microdissected cardiac muscle fiber co-localization, in situ binding assays, mutant ABHD5 functional assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction assays, in situ validation, mutagenesis with functional readout, replicated across cell types","pmids":["19064991"],"is_preprint":false},{"year":2010,"finding":"PLIN5 binds both ATGL and ABHD5, but individual PLIN5 molecules bind either ATGL or ABHD5 but not both simultaneously, suggesting an oligomeric complex at the droplet surface. The C-terminal 64 amino acids (residues 200–463) are necessary and sufficient for binding both ATGL and ABHD5, and the C-terminal region is critical for the differential binding of ATGL to PLIN5 versus PLIN1. A mutant PLIN5 that binds ABHD5 but not ATGL is defective in preventing neutral lipid accumulation.","method":"Protein interaction assays in live cells, in situ binding, chimeric/mutant perilipin analysis, neutral lipid accumulation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain mapping with mutagenesis, competition assays, and functional validation, multiple orthogonal methods in one study","pmids":["21148142"],"is_preprint":false},{"year":2012,"finding":"PLIN5 (LSDP5) overexpression in hepatocytes enhances lipid accumulation and inhibits lipolysis; knockdown decreases triglyceride content, stimulates lipolysis, and modestly increases mitochondrial fatty acid β-oxidation. The lipid droplet-targeting and droplet-clustering domain maps to the N-terminal 188 amino acids.","method":"Overexpression and siRNA knockdown in AML12 hepatocytes and primary hepatocytes, serial deletion mapping, triglyceride and lipolysis assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with metabolic readouts, domain mapping by deletions, single lab","pmids":["22675471"],"is_preprint":false},{"year":2014,"finding":"PLIN5 content is increased in isolated skeletal muscle mitochondria (~1.6-fold) following 30 min of contraction-induced lipolysis in rat hindlimb, whereas PLIN3 mitochondrial content is unchanged. An association between PLIN3 and PLIN5 was detected and was unaltered by contraction.","method":"Mitochondrial isolation by differential centrifugation, western blotting, in vivo hindlimb stimulation model","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation with functional context (contraction-induced lipolysis), single lab, single method for the key finding","pmids":["25318747"],"is_preprint":false},{"year":2019,"finding":"PLIN5 is a fatty-acid-binding protein that preferentially binds lipid droplet-derived monounsaturated fatty acids (MUFAs) and traffics them to the nucleus following cAMP/PKA-mediated lipolytic stimulation. Nuclear PLIN5 facilitates SIRT1-dependent PGC-1α/PPARα signaling. MUFAs were identified as the first endogenous allosteric activators of SIRT1 toward select substrates including PGC-1α.","method":"Fatty acid binding assays, nuclear fractionation, SIRT1 activity assays with MUFAs, cAMP/PKA stimulation, cell and animal model experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay for SIRT1 allosteric activation, direct binding assay, nuclear localization after PKA stimulation, validated in cells and animal models","pmids":["31901447"],"is_preprint":false},{"year":2020,"finding":"PLIN5 is a substrate of chaperone-mediated autophagy (CMA); its degradation through CMA (via LAMP2A) is required for lipid droplet breakdown. Disruption of CMA (LAMP2A deletion) leads to PLIN5 accumulation and impaired lipid droplet breakdown but not increased lipid droplet formation.","method":"LAMP2A-knockout mice, LAMP2A-deficient HepG2 cells (L2A−), lipid droplet quantification, PLIN5 protein measurement","journal":"Liver international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in both mice and cells with defined mechanistic pathway (CMA substrate), single lab","pmids":["32339374"],"is_preprint":false},{"year":2023,"finding":"PLIN5 interacts with the acyl-CoA synthetase FATP4 (ACSVL4) on mitochondria to promote lipid droplet-to-mitochondria fatty acid trafficking and β-oxidation during starvation. Phosphorylation of PLIN5 (by PKA during starvation) and an intact mitochondrial tethering domain are required for efficient fatty acid channeling. The C-terminal domains of PLIN5 and FATP4 constitute a minimal protein interaction sufficient to induce organelle contacts.","method":"Co-immunoprecipitation in human and murine cells, domain mapping, PLIN5 phosphorylation assays, fatty acid trafficking assays, β-oxidation measurements, organelle contact imaging","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reciprocal co-IP, domain mapping, phosphorylation-dependent functional assays, validated in human and murine cells with multiple orthogonal methods","pmids":["37290445"],"is_preprint":false},{"year":2023,"finding":"PLIN5 interacts with SERCA2 (sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2) in cardiomyocytes. Cardiac-specific PLIN5 overexpression in mice increases intracellular Ca2+ release during contraction, Ca2+ removal during relaxation, and SERCA2 function, resulting in improved cardiac contractility.","method":"Quantitative proteomics, in situ proximity ligation assay, live imaging of Ca2+ dynamics in cardiomyocytes, cardiac-specific overexpression mouse model","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — protein interaction confirmed by two orthogonal methods (proteomics + proximity ligation), functional consequence measured by live imaging, in vivo mouse model","pmids":["36717246"],"is_preprint":false},{"year":2025,"finding":"HSD17β11 facilitates the interaction between PLIN5 and ATGL, enabling efficient PKA-stimulated lipolysis in human cell lines. HSD17β11 deletion increases lipid droplet size and number due to impaired lipolysis.","method":"HSD17β11 deletion in human cell lines, co-immunoprecipitation/interaction assays for PLIN5-ATGL, lipolysis assays with PKA stimulation","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic interaction assay with functional lipolysis readout, single lab, human cell line only","pmids":["41238190"],"is_preprint":false},{"year":2025,"finding":"TBC1D15 is recruited to mitochondrial membranes in hepatocytes in response to alcohol exposure, where it recruits PLIN5 through its 10–180 aa domain, promoting mitochondria-lipid droplet contacts and facilitating PKA-induced nuclear translocation of PLIN5.","method":"TBC1D15 domain mapping, co-immunoprecipitation, immunofluorescence, hepatocyte-specific overexpression mouse model, PKA inhibition","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapped interaction with functional consequence (organelle contacts, nuclear translocation), single lab","pmids":["40334909"],"is_preprint":false},{"year":2026,"finding":"PLIN5 phosphorylation at S155 regulates mitochondria-lipid droplet contact formation in hepatocytes: the phosphorylation-resistant S155A variant enhances organelle contacts and lipid droplet expansion, while the phosphomimetic S155E variant reduces contacts and yields fewer, smaller lipid droplets. S155A overexpression in Western-diet-fed mice reduced lipotoxicity.","method":"PLIN5 phosphorylation variant overexpression (S155A, S155E), single-cell tissue imaging (scPhenomics), spatial proteomics, mouse dietary models","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — phosphorylation-site mutagenesis with organelle contact and metabolic readouts validated in vivo, multiple orthogonal methods","pmids":["41872512"],"is_preprint":false},{"year":2025,"finding":"KIF13B stabilizes PLIN5 by preventing its lysosomal degradation. Loss of KIF13B disrupts the mitochondrial localization of PLIN5, impairing cardiac lipid homeostasis and mitochondrial function. AAV9-mediated PLIN5 restoration in Kif13b-knockout mice rescued cardiac dysfunction.","method":"Kif13b knockout mice, AAV9-PLIN5 gene therapy rescue, western blotting for PLIN5 localization, immunofluorescence, lipidomics","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined molecular mechanism (lysosomal degradation, localization disruption) and rescue experiment, single lab","pmids":["41531892"],"is_preprint":false},{"year":2022,"finding":"Plin5 interacts with PGC-1α in vascular smooth muscle cells; Plin5 knockdown attenuates this interaction, increases ROS, and promotes VSMC proliferation and migration. Overexpression of PGC-1α suppresses PDGF-BB-induced ROS, proliferation, and migration in Plin5-deficient VSMCs, placing Plin5 upstream of PGC-1α in ROS regulation.","method":"Co-immunoprecipitation/interaction assay, Plin5 knockdown mice (Plin5±), VSMC isolation, ROS measurement, proliferation/migration assays, NAC rescue","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction assay combined with epistasis (PGC-1α overexpression rescues Plin5 KD phenotype), single lab","pmids":["35470759"],"is_preprint":false},{"year":2025,"finding":"PLIN5 knockdown in INS-1 β-cells promotes apoptosis and reduces insulin secretion through lipid accumulation and mitochondrial dysfunction, mediated by decreased PGC-1α and increased Drp1 levels. Reduced PLIN5 decreases binding of PGC-1α to the Drp1 promoter region, and PLIN5 overexpression reverses high-glucose-induced damage via this PGC-1α/Drp1 axis.","method":"PLIN5 knockdown and overexpression in INS-1 cells and db/db mice, chromatin interaction assay (PGC-1α binding to Drp1 promoter), mitochondrial function assays, insulin secretion measurement","journal":"Endocrine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined molecular pathway (PGC-1α/Drp1), promoter binding assay, single lab","pmids":["40884681"],"is_preprint":false},{"year":2025,"finding":"In vitro, PLIN5 incorporated into an artificial lipid droplet monolayer promotes stable attachment of large unilamellar vesicles (mimicking organelle bilayer membranes) to the droplet surface while preventing membrane fusion, demonstrating a direct role of PLIN5 protein in promoting organelle contact site formation.","method":"In vitro reconstitution with artificial lipid droplets, PLIN5-coated monolayers, LUV attachment/fusion assays with dual fluorescence labeling","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with defined components, but single study in an artificial system not yet validated in cells","pmids":["41459334"],"is_preprint":false},{"year":2024,"finding":"PLIN5 phosphorylation at S155 is increased in the lipid droplet fraction of fasted mouse liver compared to fed state (measured by mass spectrometry). The phosphorylation-resistant S155A knock-in mice show reduced IRS2 expression in liver upon fasting, suggesting phospho-PLIN5 contributes to hepatic IRS2-mediated insulin signaling, but S155 phosphorylation is dispensable for upregulation of lipid metabolism genes during fasting.","method":"Mass spectrometry quantification of phospho-PLIN5, Phos-tag gels, whole-body S155A knock-in mice, RNA sequencing, qPCR of liver gene expression","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry-confirmed phosphorylation site with in vivo genetic knock-in model, preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.11.09.622792"],"is_preprint":true},{"year":2026,"finding":"Acute deletion of PLIN5 specifically in brown adipocytes of adult mice causes reduced thermogenic gene expression, decreased mitochondrial cristae density, impaired uncoupled BAT mitochondrial respiration, and cold intolerance, establishing an essential role of BAT PLIN5 in adaptive thermogenesis.","method":"Doxycycline-inducible BAT-specific PLIN5 knockout mice, cold exposure challenge, thermogenic gene expression, transmission electron microscopy of mitochondria, mitochondrial respiration assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acute tissue-specific KO with mechanistic readouts (gene expression, mitochondrial structure, respiration), preprint not yet peer-reviewed","pmids":["41509390"],"is_preprint":true}],"current_model":"PLIN5 is a lipid droplet coat protein expressed in oxidative tissues (heart, skeletal muscle, liver, brown adipose) that acts as a scaffold to regulate lipolysis and lipid trafficking: in the basal state it sequesters ABHD5/CGI-58, limiting ATGL-mediated lipolysis, while PKA-mediated phosphorylation at S155 releases ABHD5 to activate ATGL, simultaneously promoting lipid droplet–mitochondria contact formation (tethering mitochondria via a dedicated domain and interacting with mitochondrial FATP4/ACSVL4 to channel fatty acids into β-oxidation); upon lipolytic stimulation PLIN5 also traffics monounsaturated fatty acids to the nucleus where they allosterically activate SIRT1/PGC-1α/PPARα-dependent transcription of oxidative metabolism genes, and in cardiomyocytes PLIN5 additionally interacts with SERCA2 to enhance Ca²⁺ handling and contractility."},"narrative":{"mechanistic_narrative":"PLIN5 is a lipid droplet coat protein of oxidative tissues (heart, skeletal muscle, liver, brown adipose) that scaffolds the controlled mobilization of stored triacylglycerol and couples it to mitochondrial fatty acid oxidation [PMID:17130488, PMID:16571721]. Its N-terminal PAT-1 plus adjacent 33-mer region targets the protein to the droplet surface and clusters droplets [PMID:16571721, PMID:22675471], while a C-terminal region (residues ~200–463) binds both the lipase ATGL and its co-activator ABHD5/CGI-58, with individual PLIN5 molecules engaging one or the other, implying an oligomeric regulatory complex [PMID:19064991, PMID:21148142]. In the basal state PLIN5 restrains lipolysis and promotes triacylglycerol accumulation [PMID:17234449, PMID:22675471], and productive ATGL engagement is sensitized by accessory factors including HSD17β11 [PMID:41238190]; the PLIN5–ABHD5 interaction is essential for ATGL activity at PLIN5 droplets, as an ABHD5 mutant that cannot bind PLIN5 fails to mobilize droplet lipid [PMID:19064991]. Upon cAMP/PKA-driven lipolytic stimulation PLIN5 acts as a fatty-acid-binding protein that traffics droplet-derived monounsaturated fatty acids to the nucleus, where the MUFAs allosterically activate SIRT1 toward PGC-1α and drive PGC-1α/PPARα transcriptional programs of oxidative metabolism [PMID:31901447, PMID:35470759]. PLIN5 also builds lipid droplet–mitochondria contact sites, tethering membranes directly in vitro [PMID:41459334] and channeling fatty acids into β-oxidation through its mitochondrial interaction with the acyl-CoA synthetase FATP4/ACSVL4 [PMID:37290445]; phosphorylation at S155 governs contact formation, with the phospho-resistant S155A state favoring contacts and droplet expansion and the phosphomimetic S155E state reducing them [PMID:41872512]. In cardiomyocytes PLIN5 additionally interacts with SERCA2 to enhance Ca²⁺ handling and contractility [PMID:36717246]. PLIN5 abundance and localization are set post-translationally, being degraded by chaperone-mediated autophagy via LAMP2A to permit droplet breakdown [PMID:32339374] and stabilized/positioned by the kinesin KIF13B for proper mitochondrial localization in the heart [PMID:41531892].","teleology":[{"year":2006,"claim":"Established that PLIN5 is a lipid droplet surface protein of oxidative tissues whose expression promotes triacylglycerol storage while also supporting fatty acid oxidation, defining its dual storage/oxidation role and PPARα-driven regulation.","evidence":"Subcellular fractionation, immunofluorescence and ectopic overexpression with metabolic flux in cardiomyocytes and CHO cells, plus deletion mapping and PPARα-knockout mice","pmids":["17130488","17234449","16571721"],"confidence":"Medium","gaps":["Mechanism coupling storage to oxidation not resolved","Identity of interacting lipolytic machinery unknown at this stage"]},{"year":2008,"claim":"Identified the PLIN5–ABHD5/CGI-58 interaction at the droplet surface as essential for regulating ATGL activity, explaining how PLIN5 gates lipolysis.","evidence":"Interaction assays in fibroblasts, in situ binding in microdissected cardiac fibers, and ABHD5 E262K mutant functional assays","pmids":["19064991"],"confidence":"High","gaps":["How the interaction is switched on/off by signaling not yet defined","Stoichiometry of the droplet complex unknown"]},{"year":2010,"claim":"Mapped a C-terminal region that binds ATGL and ABHD5 in a mutually exclusive manner per molecule, establishing PLIN5 as an oligomeric scaffold that differentially controls lipase recruitment.","evidence":"Live-cell interaction and competition assays, chimeric/mutant perilipin analysis, neutral lipid accumulation readouts","pmids":["21148142"],"confidence":"High","gaps":["Oligomeric architecture not structurally resolved","Regulation of the binding switch not defined"]},{"year":2012,"claim":"Confirmed via bidirectional gain/loss-of-function in hepatocytes that PLIN5 restrains lipolysis and triglyceride turnover, and localized the targeting/clustering function to the N-terminal 188 residues.","evidence":"Overexpression and siRNA in AML12 and primary hepatocytes with serial deletion mapping and metabolic assays","pmids":["22675471"],"confidence":"Medium","gaps":["Only modest effect on β-oxidation","Single-lab domain mapping"]},{"year":2014,"claim":"Showed PLIN5 redistributes to mitochondria upon contraction-induced lipolysis, providing in vivo evidence for activity-dependent droplet–mitochondria coupling.","evidence":"Mitochondrial isolation and western blotting in an in vivo rat hindlimb stimulation model","pmids":["25318747"],"confidence":"Medium","gaps":["Molecular tether mediating mitochondrial association not identified","Single method for the key finding"]},{"year":2019,"claim":"Defined a signaling output for PLIN5 beyond the droplet: it binds and shuttles MUFAs to the nucleus after PKA stimulation, where they allosterically activate SIRT1/PGC-1α/PPARα, linking lipolysis to transcriptional control of oxidative metabolism.","evidence":"Fatty acid binding assays, nuclear fractionation, in vitro SIRT1 activity assays with MUFAs, cAMP/PKA stimulation in cells and animals","pmids":["31901447"],"confidence":"High","gaps":["Mechanism of nuclear import not defined","Selectivity for MUFA species over other lipids not fully characterized"]},{"year":2020,"claim":"Established that PLIN5 abundance is controlled by chaperone-mediated autophagy, providing a degradation route required for lipid droplet breakdown.","evidence":"LAMP2A-knockout mice and LAMP2A-deficient HepG2 cells with droplet and PLIN5 protein quantification","pmids":["32339374"],"confidence":"Medium","gaps":["CMA recognition motif on PLIN5 not mapped","Relationship to phospho-regulation unknown"]},{"year":2023,"claim":"Resolved the mitochondrial tether: PLIN5 binds the acyl-CoA synthetase FATP4/ACSVL4 via C-terminal domains to form a minimal contact-inducing interaction that channels fatty acids into β-oxidation during starvation, and identified PKA phosphorylation as a requirement.","evidence":"Reciprocal co-IP in human and murine cells, domain mapping, phosphorylation and fatty acid trafficking assays, organelle contact imaging","pmids":["37290445"],"confidence":"High","gaps":["Which residue(s) drive the phospho-dependence not pinpointed in this study","Regulation of contact dynamics over time unclear"]},{"year":2023,"claim":"Extended PLIN5 function in the heart to calcium handling by demonstrating a SERCA2 interaction that enhances Ca²⁺ cycling and contractility.","evidence":"Quantitative proteomics, in situ proximity ligation assay, live Ca²⁺ imaging, cardiac-specific overexpression mice","pmids":["36717246"],"confidence":"High","gaps":["Whether interaction is direct or droplet-dependent unclear","Link to PLIN5's lipid functions not established"]},{"year":2025,"claim":"Identified accessory regulators of PLIN5 function: HSD17β11 facilitates PLIN5–ATGL interaction for PKA-stimulated lipolysis, TBC1D15 recruits PLIN5 to mitochondria to promote contacts and nuclear translocation, and KIF13B stabilizes PLIN5 against lysosomal degradation to maintain cardiac mitochondrial localization.","evidence":"Gene deletions and domain-mapped co-IP/interaction assays in human cell lines and mice, lipolysis and lipidomic readouts, AAV9-PLIN5 rescue","pmids":["41238190","40334909","41531892"],"confidence":"Medium","gaps":["Each interaction shown by single labs","Integration of these regulators into one pathway not established"]},{"year":2025,"claim":"Placed PLIN5 upstream of PGC-1α in distinct cell types, where it modulates ROS in vascular smooth muscle and a PGC-1α/Drp1 axis controlling mitochondrial function and insulin secretion in β-cells.","evidence":"Co-IP/interaction assays, knockdown/overexpression in VSMCs and INS-1 cells, Plin5± and db/db mice, promoter binding and ROS/insulin assays","pmids":["35470759","40884681"],"confidence":"Medium","gaps":["Whether PLIN5–PGC-1α interaction is direct unresolved","Tissue-specificity of the axis not reconciled"]},{"year":2025,"claim":"Provided in vitro reconstitution evidence that PLIN5 protein alone is sufficient to tether membranes to a lipid droplet monolayer while preventing fusion, confirming a direct mechanical role in contact-site formation.","evidence":"Artificial lipid droplet monolayers with PLIN5, LUV attachment/fusion assays with dual fluorescence","pmids":["41459334"],"confidence":"Medium","gaps":["Artificial system not validated in cells","Does not address regulation by phosphorylation or partners"]},{"year":2026,"claim":"Defined S155 phosphorylation as the molecular switch governing droplet–mitochondria contacts and lipotoxicity in vivo, with phospho-resistant S155A enhancing contacts and protecting against Western-diet damage and phosphomimetic S155E reducing them.","evidence":"S155A/S155E variant overexpression, single-cell tissue imaging, spatial proteomics, mouse dietary models","pmids":["41872512"],"confidence":"High","gaps":["Kinase/phosphatase dynamics at S155 in vivo not fully mapped","Reconciliation with PKA-activated lipolysis model incomplete"]},{"year":2026,"claim":"Demonstrated an essential physiological role for PLIN5 in adaptive thermogenesis through acute brown-adipocyte-specific deletion.","evidence":"Doxycycline-inducible BAT-specific knockout mice, cold challenge, thermogenic gene expression, mitochondrial EM and respiration (preprint)","pmids":["41509390"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Molecular mechanism linking PLIN5 to cristae and uncoupled respiration not defined"]},{"year":null,"claim":"How PLIN5 integrates its competing functions — lipolysis gating, mitochondrial tethering, nuclear lipid signaling, and Ca²⁺ handling — into a single phosphorylation- and partner-regulated decision at the droplet surface remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of the PLIN5 oligomeric complex","Spatiotemporal coordination between cytosolic, mitochondrial, and nuclear PLIN5 pools unknown","Phospho-code beyond S155 and its upstream kinases/phosphatases incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,9,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,11]}],"localization":[{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6,9,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,12]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,5,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8]}],"complexes":[],"partners":["ABHD5","PNPLA2","FATP4","SERCA2","PGC-1ALPHA","HSD17B11","TBC1D15","KIF13B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q00G26","full_name":"Perilipin-5","aliases":["Lipid storage droplet protein 5"],"length_aa":463,"mass_kda":50.8,"function":"Lipid droplet-associated protein that maintains the balance between lipogenesis and lipolysis and also regulates fatty acid oxidation in oxidative tissues. Recruits mitochondria to the surface of lipid droplets and is involved in lipid droplet homeostasis by regulating both the storage of fatty acids in the form of triglycerides and the release of fatty acids for mitochondrial fatty acid oxidation. In lipid droplet triacylglycerol hydrolysis, plays a role as a scaffolding protein for three major key lipolytic players: ABHD5, PNPLA2 and LIPE. Reduces the triacylglycerol hydrolase activity of PNPLA2 by recruiting and sequestering PNPLA2 to lipid droplets. Phosphorylation by PKA enables lipolysis probably by promoting release of ABHD5 from the perilipin scaffold and by facilitating interaction of ABHD5 with PNPLA2. Also increases lipolysis through interaction with LIPE and upon PKA-mediated phosphorylation of LIPE (By similarity)","subcellular_location":"Lipid droplet; Cytoplasm; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q00G26/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLIN5","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLIN5","total_profiled":1310},"omim":[{"mim_id":"613248","title":"PERILIPIN 5; PLIN5","url":"https://www.omim.org/entry/613248"},{"mim_id":"609059","title":"PATATIN-LIKE PHOSPHOLIPASE DOMAIN-CONTAINING PROTEIN 2; PNPLA2","url":"https://www.omim.org/entry/609059"},{"mim_id":"604780","title":"ABHYDROLASE DOMAIN-CONTAINING PROTEIN 5, LYSOPHOSPHATIDIC ACID ACYLTRANSFERASE; ABHD5","url":"https://www.omim.org/entry/604780"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Lipid droplets","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":199.6},{"tissue":"skeletal muscle","ntpm":142.3}],"url":"https://www.proteinatlas.org/search/PLIN5"},"hgnc":{"alias_symbol":["LSDP5","LSDA5","OXPAT","MLDP"],"prev_symbol":[]},"alphafold":{"accession":"Q00G26","domains":[{"cath_id":"-","chopping":"23-112","consensus_level":"high","plddt":68.6949,"start":23,"end":112},{"cath_id":"1.20.120.340","chopping":"207-379","consensus_level":"high","plddt":87.0211,"start":207,"end":379}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00G26","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q00G26-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q00G26-F1-predicted_aligned_error_v6.png","plddt_mean":66.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLIN5","jax_strain_url":"https://www.jax.org/strain/search?query=PLIN5"},"sequence":{"accession":"Q00G26","fasta_url":"https://rest.uniprot.org/uniprotkb/Q00G26.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q00G26/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00G26"}},"corpus_meta":[{"pmid":"17130488","id":"PMC_17130488","title":"OXPAT/PAT-1 is a PPAR-induced lipid droplet protein that promotes fatty acid utilization.","date":"2006","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/17130488","citation_count":269,"is_preprint":false},{"pmid":"17234449","id":"PMC_17234449","title":"LSDP5 is a PAT protein specifically expressed in fatty acid oxidizing tissues.","date":"2006","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17234449","citation_count":203,"is_preprint":false},{"pmid":"21148142","id":"PMC_21148142","title":"Interactions of perilipin-5 (Plin5) with adipose triglyceride lipase.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21148142","citation_count":187,"is_preprint":false},{"pmid":"16571721","id":"PMC_16571721","title":"MLDP, a novel PAT family protein localized to lipid droplets and enriched in the heart, is regulated by peroxisome proliferator-activated receptor alpha.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16571721","citation_count":179,"is_preprint":false},{"pmid":"31901447","id":"PMC_31901447","title":"Lipid Droplet-Derived Monounsaturated Fatty Acids Traffic via PLIN5 to Allosterically Activate SIRT1.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/31901447","citation_count":142,"is_preprint":false},{"pmid":"19064991","id":"PMC_19064991","title":"Functional interactions between Mldp (LSDP5) and Abhd5 in the control of intracellular lipid accumulation.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19064991","citation_count":122,"is_preprint":false},{"pmid":"37290445","id":"PMC_37290445","title":"PLIN5 interacts with FATP4 at membrane contact sites to promote lipid droplet-to-mitochondria fatty acid transport.","date":"2023","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/37290445","citation_count":112,"is_preprint":false},{"pmid":"19602560","id":"PMC_19602560","title":"Adipocyte differentiation-related protein and OXPAT in rat and human skeletal muscle: involvement in lipid accumulation and type 2 diabetes mellitus.","date":"2009","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/19602560","citation_count":83,"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. 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Ectopic expression promotes fatty acid-induced triacylglycerol accumulation and long-chain fatty acid oxidation.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence co-localization in primary cardiomyocytes, ectopic overexpression with metabolic flux assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fractionation and imaging, functional consequence shown by overexpression with metabolic readouts, single lab\",\n      \"pmids\": [\"17130488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PLIN5 (LSDP5) associates with lipid storage droplets when ectopically expressed as YFP or FLAG fusion proteins, and forced expression in CHO cells inhibits lipolysis of intracellular lipid droplets.\",\n      \"method\": \"Fluorescent fusion protein expression, lipid droplet fractionation, lipolysis assay in CHO cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (lipolysis inhibition), single lab, two orthogonal methods\",\n      \"pmids\": [\"17234449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PLIN5 (MLDP) is enriched on lipid droplet surfaces in the heart; the N-terminal PAT-1 domain plus the adjacent 33-mer domain are required for lipid droplet targeting. Expression is regulated by PPARalpha and induced by fasting.\",\n      \"method\": \"GFP fusion protein overexpression, deletion analysis, subcellular fractionation, PPARalpha knockout mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping via deletion mutants with direct localization readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"16571721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PLIN5 (Mldp) binds ABHD5 (CGI-58, the co-activator of ATGL) on the surface of lipid droplets in cardiac muscle fibers. This interaction is dynamic, enhanced by oleic acid treatment in a triglyceride-synthesis-dependent manner, and essential for ATGL activity at PLIN5-containing lipid droplets; an ABHD5 mutant (E262K) that cannot bind PLIN5 fails to prevent lipid droplet accumulation in cells expressing PLIN5.\",\n      \"method\": \"Protein interaction assays in transfected fibroblasts, microdissected cardiac muscle fiber co-localization, in situ binding assays, mutant ABHD5 functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction assays, in situ validation, mutagenesis with functional readout, replicated across cell types\",\n      \"pmids\": [\"19064991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PLIN5 binds both ATGL and ABHD5, but individual PLIN5 molecules bind either ATGL or ABHD5 but not both simultaneously, suggesting an oligomeric complex at the droplet surface. The C-terminal 64 amino acids (residues 200–463) are necessary and sufficient for binding both ATGL and ABHD5, and the C-terminal region is critical for the differential binding of ATGL to PLIN5 versus PLIN1. A mutant PLIN5 that binds ABHD5 but not ATGL is defective in preventing neutral lipid accumulation.\",\n      \"method\": \"Protein interaction assays in live cells, in situ binding, chimeric/mutant perilipin analysis, neutral lipid accumulation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain mapping with mutagenesis, competition assays, and functional validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21148142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PLIN5 (LSDP5) overexpression in hepatocytes enhances lipid accumulation and inhibits lipolysis; knockdown decreases triglyceride content, stimulates lipolysis, and modestly increases mitochondrial fatty acid β-oxidation. The lipid droplet-targeting and droplet-clustering domain maps to the N-terminal 188 amino acids.\",\n      \"method\": \"Overexpression and siRNA knockdown in AML12 hepatocytes and primary hepatocytes, serial deletion mapping, triglyceride and lipolysis assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with metabolic readouts, domain mapping by deletions, single lab\",\n      \"pmids\": [\"22675471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PLIN5 content is increased in isolated skeletal muscle mitochondria (~1.6-fold) following 30 min of contraction-induced lipolysis in rat hindlimb, whereas PLIN3 mitochondrial content is unchanged. An association between PLIN3 and PLIN5 was detected and was unaltered by contraction.\",\n      \"method\": \"Mitochondrial isolation by differential centrifugation, western blotting, in vivo hindlimb stimulation model\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation with functional context (contraction-induced lipolysis), single lab, single method for the key finding\",\n      \"pmids\": [\"25318747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLIN5 is a fatty-acid-binding protein that preferentially binds lipid droplet-derived monounsaturated fatty acids (MUFAs) and traffics them to the nucleus following cAMP/PKA-mediated lipolytic stimulation. Nuclear PLIN5 facilitates SIRT1-dependent PGC-1α/PPARα signaling. MUFAs were identified as the first endogenous allosteric activators of SIRT1 toward select substrates including PGC-1α.\",\n      \"method\": \"Fatty acid binding assays, nuclear fractionation, SIRT1 activity assays with MUFAs, cAMP/PKA stimulation, cell and animal model experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay for SIRT1 allosteric activation, direct binding assay, nuclear localization after PKA stimulation, validated in cells and animal models\",\n      \"pmids\": [\"31901447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PLIN5 is a substrate of chaperone-mediated autophagy (CMA); its degradation through CMA (via LAMP2A) is required for lipid droplet breakdown. Disruption of CMA (LAMP2A deletion) leads to PLIN5 accumulation and impaired lipid droplet breakdown but not increased lipid droplet formation.\",\n      \"method\": \"LAMP2A-knockout mice, LAMP2A-deficient HepG2 cells (L2A−), lipid droplet quantification, PLIN5 protein measurement\",\n      \"journal\": \"Liver international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in both mice and cells with defined mechanistic pathway (CMA substrate), single lab\",\n      \"pmids\": [\"32339374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLIN5 interacts with the acyl-CoA synthetase FATP4 (ACSVL4) on mitochondria to promote lipid droplet-to-mitochondria fatty acid trafficking and β-oxidation during starvation. Phosphorylation of PLIN5 (by PKA during starvation) and an intact mitochondrial tethering domain are required for efficient fatty acid channeling. The C-terminal domains of PLIN5 and FATP4 constitute a minimal protein interaction sufficient to induce organelle contacts.\",\n      \"method\": \"Co-immunoprecipitation in human and murine cells, domain mapping, PLIN5 phosphorylation assays, fatty acid trafficking assays, β-oxidation measurements, organelle contact imaging\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reciprocal co-IP, domain mapping, phosphorylation-dependent functional assays, validated in human and murine cells with multiple orthogonal methods\",\n      \"pmids\": [\"37290445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLIN5 interacts with SERCA2 (sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2) in cardiomyocytes. Cardiac-specific PLIN5 overexpression in mice increases intracellular Ca2+ release during contraction, Ca2+ removal during relaxation, and SERCA2 function, resulting in improved cardiac contractility.\",\n      \"method\": \"Quantitative proteomics, in situ proximity ligation assay, live imaging of Ca2+ dynamics in cardiomyocytes, cardiac-specific overexpression mouse model\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — protein interaction confirmed by two orthogonal methods (proteomics + proximity ligation), functional consequence measured by live imaging, in vivo mouse model\",\n      \"pmids\": [\"36717246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HSD17β11 facilitates the interaction between PLIN5 and ATGL, enabling efficient PKA-stimulated lipolysis in human cell lines. HSD17β11 deletion increases lipid droplet size and number due to impaired lipolysis.\",\n      \"method\": \"HSD17β11 deletion in human cell lines, co-immunoprecipitation/interaction assays for PLIN5-ATGL, lipolysis assays with PKA stimulation\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic interaction assay with functional lipolysis readout, single lab, human cell line only\",\n      \"pmids\": [\"41238190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TBC1D15 is recruited to mitochondrial membranes in hepatocytes in response to alcohol exposure, where it recruits PLIN5 through its 10–180 aa domain, promoting mitochondria-lipid droplet contacts and facilitating PKA-induced nuclear translocation of PLIN5.\",\n      \"method\": \"TBC1D15 domain mapping, co-immunoprecipitation, immunofluorescence, hepatocyte-specific overexpression mouse model, PKA inhibition\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapped interaction with functional consequence (organelle contacts, nuclear translocation), single lab\",\n      \"pmids\": [\"40334909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PLIN5 phosphorylation at S155 regulates mitochondria-lipid droplet contact formation in hepatocytes: the phosphorylation-resistant S155A variant enhances organelle contacts and lipid droplet expansion, while the phosphomimetic S155E variant reduces contacts and yields fewer, smaller lipid droplets. S155A overexpression in Western-diet-fed mice reduced lipotoxicity.\",\n      \"method\": \"PLIN5 phosphorylation variant overexpression (S155A, S155E), single-cell tissue imaging (scPhenomics), spatial proteomics, mouse dietary models\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — phosphorylation-site mutagenesis with organelle contact and metabolic readouts validated in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"41872512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIF13B stabilizes PLIN5 by preventing its lysosomal degradation. Loss of KIF13B disrupts the mitochondrial localization of PLIN5, impairing cardiac lipid homeostasis and mitochondrial function. AAV9-mediated PLIN5 restoration in Kif13b-knockout mice rescued cardiac dysfunction.\",\n      \"method\": \"Kif13b knockout mice, AAV9-PLIN5 gene therapy rescue, western blotting for PLIN5 localization, immunofluorescence, lipidomics\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined molecular mechanism (lysosomal degradation, localization disruption) and rescue experiment, single lab\",\n      \"pmids\": [\"41531892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Plin5 interacts with PGC-1α in vascular smooth muscle cells; Plin5 knockdown attenuates this interaction, increases ROS, and promotes VSMC proliferation and migration. Overexpression of PGC-1α suppresses PDGF-BB-induced ROS, proliferation, and migration in Plin5-deficient VSMCs, placing Plin5 upstream of PGC-1α in ROS regulation.\",\n      \"method\": \"Co-immunoprecipitation/interaction assay, Plin5 knockdown mice (Plin5±), VSMC isolation, ROS measurement, proliferation/migration assays, NAC rescue\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction assay combined with epistasis (PGC-1α overexpression rescues Plin5 KD phenotype), single lab\",\n      \"pmids\": [\"35470759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PLIN5 knockdown in INS-1 β-cells promotes apoptosis and reduces insulin secretion through lipid accumulation and mitochondrial dysfunction, mediated by decreased PGC-1α and increased Drp1 levels. Reduced PLIN5 decreases binding of PGC-1α to the Drp1 promoter region, and PLIN5 overexpression reverses high-glucose-induced damage via this PGC-1α/Drp1 axis.\",\n      \"method\": \"PLIN5 knockdown and overexpression in INS-1 cells and db/db mice, chromatin interaction assay (PGC-1α binding to Drp1 promoter), mitochondrial function assays, insulin secretion measurement\",\n      \"journal\": \"Endocrine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined molecular pathway (PGC-1α/Drp1), promoter binding assay, single lab\",\n      \"pmids\": [\"40884681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In vitro, PLIN5 incorporated into an artificial lipid droplet monolayer promotes stable attachment of large unilamellar vesicles (mimicking organelle bilayer membranes) to the droplet surface while preventing membrane fusion, demonstrating a direct role of PLIN5 protein in promoting organelle contact site formation.\",\n      \"method\": \"In vitro reconstitution with artificial lipid droplets, PLIN5-coated monolayers, LUV attachment/fusion assays with dual fluorescence labeling\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with defined components, but single study in an artificial system not yet validated in cells\",\n      \"pmids\": [\"41459334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLIN5 phosphorylation at S155 is increased in the lipid droplet fraction of fasted mouse liver compared to fed state (measured by mass spectrometry). The phosphorylation-resistant S155A knock-in mice show reduced IRS2 expression in liver upon fasting, suggesting phospho-PLIN5 contributes to hepatic IRS2-mediated insulin signaling, but S155 phosphorylation is dispensable for upregulation of lipid metabolism genes during fasting.\",\n      \"method\": \"Mass spectrometry quantification of phospho-PLIN5, Phos-tag gels, whole-body S155A knock-in mice, RNA sequencing, qPCR of liver gene expression\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry-confirmed phosphorylation site with in vivo genetic knock-in model, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.11.09.622792\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Acute deletion of PLIN5 specifically in brown adipocytes of adult mice causes reduced thermogenic gene expression, decreased mitochondrial cristae density, impaired uncoupled BAT mitochondrial respiration, and cold intolerance, establishing an essential role of BAT PLIN5 in adaptive thermogenesis.\",\n      \"method\": \"Doxycycline-inducible BAT-specific PLIN5 knockout mice, cold exposure challenge, thermogenic gene expression, transmission electron microscopy of mitochondria, mitochondrial respiration assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acute tissue-specific KO with mechanistic readouts (gene expression, mitochondrial structure, respiration), preprint not yet peer-reviewed\",\n      \"pmids\": [\"41509390\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PLIN5 is a lipid droplet coat protein expressed in oxidative tissues (heart, skeletal muscle, liver, brown adipose) that acts as a scaffold to regulate lipolysis and lipid trafficking: in the basal state it sequesters ABHD5/CGI-58, limiting ATGL-mediated lipolysis, while PKA-mediated phosphorylation at S155 releases ABHD5 to activate ATGL, simultaneously promoting lipid droplet–mitochondria contact formation (tethering mitochondria via a dedicated domain and interacting with mitochondrial FATP4/ACSVL4 to channel fatty acids into β-oxidation); upon lipolytic stimulation PLIN5 also traffics monounsaturated fatty acids to the nucleus where they allosterically activate SIRT1/PGC-1α/PPARα-dependent transcription of oxidative metabolism genes, and in cardiomyocytes PLIN5 additionally interacts with SERCA2 to enhance Ca²⁺ handling and contractility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLIN5 is a lipid droplet coat protein of oxidative tissues (heart, skeletal muscle, liver, brown adipose) that scaffolds the controlled mobilization of stored triacylglycerol and couples it to mitochondrial fatty acid oxidation [#0, #2]. Its N-terminal PAT-1 plus adjacent 33-mer region targets the protein to the droplet surface and clusters droplets [#2, #5], while a C-terminal region (residues ~200–463) binds both the lipase ATGL and its co-activator ABHD5/CGI-58, with individual PLIN5 molecules engaging one or the other, implying an oligomeric regulatory complex [#3, #4]. In the basal state PLIN5 restrains lipolysis and promotes triacylglycerol accumulation [#1, #5], and productive ATGL engagement is sensitized by accessory factors including HSD17β11 [#11]; the PLIN5–ABHD5 interaction is essential for ATGL activity at PLIN5 droplets, as an ABHD5 mutant that cannot bind PLIN5 fails to mobilize droplet lipid [#3]. Upon cAMP/PKA-driven lipolytic stimulation PLIN5 acts as a fatty-acid-binding protein that traffics droplet-derived monounsaturated fatty acids to the nucleus, where the MUFAs allosterically activate SIRT1 toward PGC-1α and drive PGC-1α/PPARα transcriptional programs of oxidative metabolism [#7, #15]. PLIN5 also builds lipid droplet–mitochondria contact sites, tethering membranes directly in vitro [#17] and channeling fatty acids into β-oxidation through its mitochondrial interaction with the acyl-CoA synthetase FATP4/ACSVL4 [#9]; phosphorylation at S155 governs contact formation, with the phospho-resistant S155A state favoring contacts and droplet expansion and the phosphomimetic S155E state reducing them [#13]. In cardiomyocytes PLIN5 additionally interacts with SERCA2 to enhance Ca²⁺ handling and contractility [#10]. PLIN5 abundance and localization are set post-translationally, being degraded by chaperone-mediated autophagy via LAMP2A to permit droplet breakdown [#8] and stabilized/positioned by the kinesin KIF13B for proper mitochondrial localization in the heart [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that PLIN5 is a lipid droplet surface protein of oxidative tissues whose expression promotes triacylglycerol storage while also supporting fatty acid oxidation, defining its dual storage/oxidation role and PPARα-driven regulation.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence and ectopic overexpression with metabolic flux in cardiomyocytes and CHO cells, plus deletion mapping and PPARα-knockout mice\",\n      \"pmids\": [\"17130488\", \"17234449\", \"16571721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling storage to oxidation not resolved\", \"Identity of interacting lipolytic machinery unknown at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the PLIN5–ABHD5/CGI-58 interaction at the droplet surface as essential for regulating ATGL activity, explaining how PLIN5 gates lipolysis.\",\n      \"evidence\": \"Interaction assays in fibroblasts, in situ binding in microdissected cardiac fibers, and ABHD5 E262K mutant functional assays\",\n      \"pmids\": [\"19064991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the interaction is switched on/off by signaling not yet defined\", \"Stoichiometry of the droplet complex unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped a C-terminal region that binds ATGL and ABHD5 in a mutually exclusive manner per molecule, establishing PLIN5 as an oligomeric scaffold that differentially controls lipase recruitment.\",\n      \"evidence\": \"Live-cell interaction and competition assays, chimeric/mutant perilipin analysis, neutral lipid accumulation readouts\",\n      \"pmids\": [\"21148142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Oligomeric architecture not structurally resolved\", \"Regulation of the binding switch not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Confirmed via bidirectional gain/loss-of-function in hepatocytes that PLIN5 restrains lipolysis and triglyceride turnover, and localized the targeting/clustering function to the N-terminal 188 residues.\",\n      \"evidence\": \"Overexpression and siRNA in AML12 and primary hepatocytes with serial deletion mapping and metabolic assays\",\n      \"pmids\": [\"22675471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only modest effect on β-oxidation\", \"Single-lab domain mapping\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed PLIN5 redistributes to mitochondria upon contraction-induced lipolysis, providing in vivo evidence for activity-dependent droplet–mitochondria coupling.\",\n      \"evidence\": \"Mitochondrial isolation and western blotting in an in vivo rat hindlimb stimulation model\",\n      \"pmids\": [\"25318747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular tether mediating mitochondrial association not identified\", \"Single method for the key finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a signaling output for PLIN5 beyond the droplet: it binds and shuttles MUFAs to the nucleus after PKA stimulation, where they allosterically activate SIRT1/PGC-1α/PPARα, linking lipolysis to transcriptional control of oxidative metabolism.\",\n      \"evidence\": \"Fatty acid binding assays, nuclear fractionation, in vitro SIRT1 activity assays with MUFAs, cAMP/PKA stimulation in cells and animals\",\n      \"pmids\": [\"31901447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear import not defined\", \"Selectivity for MUFA species over other lipids not fully characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that PLIN5 abundance is controlled by chaperone-mediated autophagy, providing a degradation route required for lipid droplet breakdown.\",\n      \"evidence\": \"LAMP2A-knockout mice and LAMP2A-deficient HepG2 cells with droplet and PLIN5 protein quantification\",\n      \"pmids\": [\"32339374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CMA recognition motif on PLIN5 not mapped\", \"Relationship to phospho-regulation unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the mitochondrial tether: PLIN5 binds the acyl-CoA synthetase FATP4/ACSVL4 via C-terminal domains to form a minimal contact-inducing interaction that channels fatty acids into β-oxidation during starvation, and identified PKA phosphorylation as a requirement.\",\n      \"evidence\": \"Reciprocal co-IP in human and murine cells, domain mapping, phosphorylation and fatty acid trafficking assays, organelle contact imaging\",\n      \"pmids\": [\"37290445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which residue(s) drive the phospho-dependence not pinpointed in this study\", \"Regulation of contact dynamics over time unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended PLIN5 function in the heart to calcium handling by demonstrating a SERCA2 interaction that enhances Ca²⁺ cycling and contractility.\",\n      \"evidence\": \"Quantitative proteomics, in situ proximity ligation assay, live Ca²⁺ imaging, cardiac-specific overexpression mice\",\n      \"pmids\": [\"36717246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether interaction is direct or droplet-dependent unclear\", \"Link to PLIN5's lipid functions not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified accessory regulators of PLIN5 function: HSD17β11 facilitates PLIN5–ATGL interaction for PKA-stimulated lipolysis, TBC1D15 recruits PLIN5 to mitochondria to promote contacts and nuclear translocation, and KIF13B stabilizes PLIN5 against lysosomal degradation to maintain cardiac mitochondrial localization.\",\n      \"evidence\": \"Gene deletions and domain-mapped co-IP/interaction assays in human cell lines and mice, lipolysis and lipidomic readouts, AAV9-PLIN5 rescue\",\n      \"pmids\": [\"41238190\", \"40334909\", \"41531892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each interaction shown by single labs\", \"Integration of these regulators into one pathway not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed PLIN5 upstream of PGC-1α in distinct cell types, where it modulates ROS in vascular smooth muscle and a PGC-1α/Drp1 axis controlling mitochondrial function and insulin secretion in β-cells.\",\n      \"evidence\": \"Co-IP/interaction assays, knockdown/overexpression in VSMCs and INS-1 cells, Plin5± and db/db mice, promoter binding and ROS/insulin assays\",\n      \"pmids\": [\"35470759\", \"40884681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PLIN5–PGC-1α interaction is direct unresolved\", \"Tissue-specificity of the axis not reconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided in vitro reconstitution evidence that PLIN5 protein alone is sufficient to tether membranes to a lipid droplet monolayer while preventing fusion, confirming a direct mechanical role in contact-site formation.\",\n      \"evidence\": \"Artificial lipid droplet monolayers with PLIN5, LUV attachment/fusion assays with dual fluorescence\",\n      \"pmids\": [\"41459334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Artificial system not validated in cells\", \"Does not address regulation by phosphorylation or partners\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined S155 phosphorylation as the molecular switch governing droplet–mitochondria contacts and lipotoxicity in vivo, with phospho-resistant S155A enhancing contacts and protecting against Western-diet damage and phosphomimetic S155E reducing them.\",\n      \"evidence\": \"S155A/S155E variant overexpression, single-cell tissue imaging, spatial proteomics, mouse dietary models\",\n      \"pmids\": [\"41872512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase/phosphatase dynamics at S155 in vivo not fully mapped\", \"Reconciliation with PKA-activated lipolysis model incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated an essential physiological role for PLIN5 in adaptive thermogenesis through acute brown-adipocyte-specific deletion.\",\n      \"evidence\": \"Doxycycline-inducible BAT-specific knockout mice, cold challenge, thermogenic gene expression, mitochondrial EM and respiration (preprint)\",\n      \"pmids\": [\"41509390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Molecular mechanism linking PLIN5 to cristae and uncoupled respiration not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PLIN5 integrates its competing functions — lipolysis gating, mitochondrial tethering, nuclear lipid signaling, and Ca²⁺ handling — into a single phosphorylation- and partner-regulated decision at the droplet surface remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of the PLIN5 oligomeric complex\", \"Spatiotemporal coordination between cytosolic, mitochondrial, and nuclear PLIN5 pools unknown\", \"Phospho-code beyond S155 and its upstream kinases/phosphatases incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 9, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6, 9, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ABHD5\", \"PNPLA2\", \"FATP4\", \"SERCA2\", \"PGC-1alpha\", \"HSD17B11\", \"TBC1D15\", \"KIF13B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}