PLIN4

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.

1. 2003 High

   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

   PMID:12840023

   Open questions at the time

   • Did not define the targeting motif on PLIN4 that mediates droplet binding
   • Mechanism linking insulin signaling to recruitment not resolved
2. 2004 Medium

   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

   PMID:15111493

   Open questions at the time

   • Single-lab promoter analysis
   • Does not address post-transcriptional regulation of PLIN4
3. 2005 High

   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

   PMID:15731108

   Open questions at the time

   • Molecular signal triggering cytosol-to-droplet recruitment not identified
   • Functional consequence of the peripheral vs. medial droplet segregation unknown
4. 2013 High

   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

   PMID:23423172

   Open questions at the time

   • Mechanism by which PLIN4 controls Plin5 protein levels unresolved
   • Tissue specificity of the cardiac phenotype unexplained
5. 2018 Medium

   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

   PMID:29967574

   Open questions at the time

   • How lipid droplets mechanistically block the parkin-p62 axis not defined
   • Single-lab model system
6. 2022 Medium

   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

   PMID:35390677

   Open questions at the time

   • Direct PLIN4–HSC70 binding interface not mapped
   • Whether SH2B1 binds PLIN4 directly versus via HSC70 unresolved
7. 2024 Medium

   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

   PMID:38677512

   Open questions at the time

   • SUMOylation site(s) on PLIN4 not specified
   • How SUMO status alters droplet affinity mechanistically unknown
8. 2024 Medium

   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

   PMID:39173539

   Open questions at the time

   • Direct m6A sites on PLIN4 transcript not mapped
   • Causal chain from lipid droplets to ferroptotic lipid peroxidation incompletely defined
9. 2025 Medium

   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

   PMID:41391763

   Open questions at the time

   • Mechanistic link between PLIN4 and PERK ER stress signaling unresolved
   • Cause of adipose inflammatory phenotype not established
10. 2025 Medium

    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)

    Open questions at the time

    • 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

• 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.
• 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