PLIN4

PLIN4 is a PPARγ-regulated lipid droplet coat protein whose tandem 33-amino-acid amphipathic helix repeats enable rapid, reversible association with nascent triacylglycerol-rich lipid droplets in adipocytes and other cell types (PMID:12840023, PMID:15111493). Its lipid droplet targeting is controlled post-translationally by SENP7-mediated deSUMOylation, and in the cytosol PLIN4 is turned over via HSC70-dependent lysosomal degradation promoted by SH2B1 (PMID:38677512, PMID:35390677). At the organismal level, Plin4 deficiency reduces cardiac and hepatic triacylglycerol storage—partly by downregulating Plin5 in the heart—and modulates ER stress and adipose inflammation under dietary stress, while excess PLIN4-dependent lipid droplet accumulation in neurons inhibits parkin–p62-mediated mitophagy and promotes ferroptosis (PMID:23423172, PMID:41391763, PMID:29967574, PMID:39173539). The ~1000-amino-acid repetitive amphipathic helix domain can form amyloid fibrils in vitro, and repeat expansion linked to autosomal dominant vacuolar myopathy accelerates this fibrillation, with lipid droplet binding and amyloid self-assembly representing competing fates for the protein (PMID:12840023).

1. 2003 High

   Establishing that PLIN4 is a lipid droplet coat protein resolved its subcellular function: it redistributes from the cytoplasm to nascent peripheral lipid droplets upon fatty acid loading, in a triacylglycerol synthesis–dependent manner.

   Evidence Immunofluorescence of oleate-treated 3T3-L1 adipocytes with triacylglycerol synthesis inhibitor

   PMID:12840023

   Open questions at the time

   • Mechanism by which PLIN4 selectively targets nascent versus mature lipid droplets was not defined
   • Structural basis of the amphipathic helix–lipid droplet interaction not resolved
2. 2004 High

   Identifying PLIN4 as a direct PPARγ transcriptional target explained its adipose-enriched expression and linked it to the master adipogenic program.

   Evidence Promoter-reporter assays identifying three conserved PPREs; expression analysis in adipocytes and Zucker rats

   PMID:15111493

   Open questions at the time

   • Whether additional transcription factors cooperate with PPARγ at the PLIN4 locus was not tested
   • Regulation in non-adipose tissues not addressed
3. 2005 High

   Demonstrating that PLIN4 belongs to a pre-existing cytosolic reservoir of coat proteins (with adipophilin and TIP47) that package triacylglycerol without new protein synthesis established a rapid-response lipid storage mechanism.

   Evidence Subcellular fractionation and cycloheximide treatment of oleate-loaded 3T3-L1 adipocytes

   PMID:15731108

   Open questions at the time

   • Functional redundancy or hierarchy among the three coat proteins was not resolved
   • Post-translational signals controlling redistribution were unknown
4. 2013 High

   The Plin4 knockout mouse revealed an unexpected tissue-specific role in the heart: Plin4 loss reduced cardiac triacylglycerol and dramatically decreased Plin5 expression, linking PLIN4 to cardiac lipid homeostasis beyond a simple coat function.

   Evidence Gene-targeted Plin4−/− mice subjected to fasting, high-fat diet, and leptin-deficiency challenges with cardiac lipid quantification and qPCR

   PMID:23423172

   Open questions at the time

   • Mechanism by which Plin4 controls Plin5 transcription in the heart is unknown
   • Whether cardiac protection from steatosis translates to functional cardiac benefit was not assessed
5. 2018 Medium

   Placing PLIN4-dependent lipid droplet accumulation upstream of impaired parkin–ubiquitin–p62 mitophagy in dopaminergic neurons provided a mechanistic link between lipid storage and neurodegeneration in a Parkinson's disease model.

   Evidence Plin4 siRNA in SH-SY5Y cells and primary neurons; MPTP/p mouse model with TH-neuron quantification

   PMID:29967574

   Open questions at the time

   • Whether PLIN4-coated lipid droplets physically sequester parkin or p62 was not shown
   • Not independently replicated
   • Causal direction between lipid droplet excess and mitophagy inhibition not fully dissected
6. 2019 Medium

   Demonstrating that PLIN4 is required for lipid droplet stability and viability in chemoresistant triple-negative breast cancer cells extended its functional significance to cancer biology.

   Evidence PLIN4 siRNA in MDA-MB-436 chemoresistant cells with lipid droplet imaging and viability assays

   PMID:31537618

   Open questions at the time

   • Mechanistic basis of chemoresistance dependence on PLIN4-coated lipid droplets was not elucidated
   • Limited to a single cell line
7. 2022 Medium

   Identifying SH2B1 as a recruiter of HSC70 that drives lysosomal degradation of PLIN4 defined a post-translational clearance pathway and explained how PLIN4 protein levels are constrained to prevent lipid peroxidation and neuronal apoptosis.

   Evidence Co-IP of SH2B1–HSC70; Sh2b1 KO and neuron-specific overexpression in MPTP mice; AAV-HSC70 rescue

   PMID:35390677

   Open questions at the time

   • Direct ubiquitin or chaperone-mediated autophagy signals on PLIN4 were not mapped
   • Whether this degradation pathway operates in non-neuronal tissues is untested
8. 2024 Medium

   Showing that SENP7-mediated deSUMOylation is required for PLIN4 lipid droplet targeting resolved a key post-translational switch: SUMOylated PLIN4 fails to coat droplets, resulting in smaller droplets and reduced adipose mass.

   Evidence Conventional and adipocyte-specific Senp7 KO mice; biochemical deSUMOylation assay

   PMID:38677512

   Open questions at the time

   • Specific SUMO-modified residues on PLIN4 were not identified
   • Whether SUMOylation affects PLIN4 stability or only localization is unclear
   • Not independently replicated
9. 2024 Medium

   Demonstrating that PLIN4 upregulation promotes ferroptosis in Leydig cells (via cadmium/m6A pathway) and hippocampal neurons (via sevoflurane) broadened PLIN4's pathological roles to iron-dependent cell death across tissues.

   Evidence Plin4 siRNA in Leydig cells with Fe²⁺ and lipid droplet quantification; PLIN4 KD/OE in HT22 hippocampal cells with ferroptosis markers

   PMID:39173539 PMID:39182851

   Open questions at the time

   • Direct mechanism linking PLIN4/lipid droplets to lipid peroxidation and iron metabolism is not defined
   • Hippo pathway connection (PMID:39182851) is correlative with low confidence
10. 2025 Medium

    Plin4 knockout in diet-obese female mice revealed a hepatoprotective role: Plin4 loss reduced hepatic triacylglycerol and PERK-dependent ER stress, but increased adipose inflammation, suggesting tissue-opposing metabolic functions.

    Evidence Plin4−/− mice on Western diet; hepatic lipid quantification, ER stress markers, adipose histology

    PMID:41391763

    Open questions at the time

    • Link between PLIN4 and PERK pathway is correlative
    • Mechanism of increased adipose inflammation in the absence of Plin4 is unknown
    • Sex-specific effects not tested in males
11. 2025 Medium

    Structural demonstration that the PLIN4 tandem 33-aa amphipathic helix repeat domain forms amyloid fibrils—accelerated by disease-associated repeat expansion—and that lipid droplet binding competes with fibrillation provided a molecular mechanism for PLIN4 repeat-expansion vacuolar myopathy.

    Evidence (preprint) Cryo-EM, atomic force microscopy of purified repeat fragments; fibrillation kinetics; cell-based lipid droplet binding competition assay

    Open questions at the time

    • Not yet peer-reviewed
    • In vivo fibril formation in patient muscle not demonstrated
    • Repeat expansion threshold for clinical disease not defined

• The precise structural basis by which PLIN4 amphipathic helices coat lipid droplet monolayers, the SUMO acceptor sites controlling its localization, the mechanism linking PLIN4-coated droplets to ferroptosis and mitophagy inhibition, and the in vivo relevance of amyloid fibril formation in myopathy remain open questions.
• No high-resolution structure of PLIN4 on a lipid droplet surface
• SUMO modification sites unmapped
• Causal mechanism connecting lipid droplet coating to iron-dependent cell death not established
• Patient tissue confirmation of amyloid fibrils absent