Affinage

BSCL2

Seipin · UniProt Q96G97

Length
398 aa
Mass
44.4 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Seipin (BSCL2) is an ER-resident integral membrane protein that oligomerizes into ring-shaped assemblies of 9–12 subunits at ER–lipid droplet junctions, where it nucleates lipid droplet (LD) biogenesis by concentrating triacylglycerol and other neutral lipids within its lumenal β-sandwich domain and transmembrane cage, thereby defining LD formation sites, stabilizing ER–LD neck contacts, and preventing aberrant LD ripening (PMID:18093937, PMID:30293840, PMID:35938957, PMID:31178403). Seipin scaffolds consecutive glycerolipid biosynthetic enzymes—AGPAT2, lipin 1, and GPAT3—at the ER membrane during adipogenesis, and restrains cAMP/PKA-mediated lipolysis and ATGL-dependent lipid mobilization, thereby enabling terminal adipocyte differentiation; loss-of-function mutations cause Berardinelli–Seip congenital generalized lipodystrophy type 2 (PMID:24026679, PMID:25737955, PMID:27806294, PMID:22269949, PMID:31185001). A subset of seipin localizes to ER–mitochondria contact sites where it facilitates mitochondrial calcium import required for TCA cycle flux and lipogenesis (PMID:30049710, PMID:35021082). Dominant N-glycosylation-disrupting mutations (N88S, S90L) cause seipin misfolding, ER stress via calnexin sequestration, and motor neuropathy (dHMN-V/Silver syndrome) (PMID:14981520, PMID:17387721).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 High

    The discovery that heterozygous N88S/S90L mutations disrupt seipin N-glycosylation and cause ER aggregation established that BSCL2 mutations can act dominantly through a protein misfolding mechanism, linking seipin to hereditary motor neuropathy.

    Evidence Mutation identification in multiple families, glycosylation assays, and aggregate detection in transfected cells

    PMID:14981520

    Open questions at the time
    • Mechanism by which aggregates specifically damage motor neurons unknown
    • Whether aggregation triggers neurodegeneration via gain-of-function toxicity versus loss of seipin function unresolved
  2. 2006 High

    Topology mapping established seipin as a two-pass ER transmembrane protein with a large lumenal loop and cytoplasmic N- and C-termini, defining the structural framework for subsequent functional studies.

    Evidence In vitro topology mapping assay

    PMID:16574104

    Open questions at the time
    • Structural basis of the lumenal domain not yet resolved
    • Post-translational modifications beyond N-glycosylation uncharacterized
  3. 2007 High

    Two studies established that seipin concentrates at ER–LD junctions and that its absence causes aberrant LD morphology, while neuropathy-mutant seipin undergoes ERAD and triggers ER stress via stable calnexin binding, separating lipodystrophy from neuropathy mechanisms.

    Evidence Yeast seipin-GFP imaging and cross-species complementation (LD phenotype); co-immunoprecipitation with calnexin, ubiquitination, and apoptosis assays in neuronal cells (ER stress)

    PMID:17387721 PMID:18093937

    Open questions at the time
    • Whether seipin directly contacts lipid or acts indirectly unknown
    • Molecular basis of ER–LD junction stabilization unresolved
  4. 2008 High

    Cell-autonomous requirement of seipin for adipocyte differentiation was demonstrated, with seipin knockdown impairing PPARγ/C/EBPα expression and triglyceride synthesis gene induction, while yeast studies showed seipin controls LD size by preventing LD–LD fusion and altering phospholipid composition.

    Evidence shRNA knockdown in mesenchymal stem cells with adipogenic readouts; yeast genome-wide screen with LD fusion assays and lipidomics

    PMID:18250201 PMID:18458148

    Open questions at the time
    • Direct mechanism linking seipin to PPARγ maintenance unknown
    • Whether phospholipid changes are cause or consequence of LD defects unclear
  5. 2011 High

    Seipin was shown to form homo-oligomeric toroidal complexes (~9–12-mers), and Bscl2-knockout mouse studies revealed that unrestrained cAMP/PKA-mediated lipolysis—not failure of early adipogenic transcription—causes terminal differentiation failure, rescuable by lipolysis inhibition.

    Evidence Purification with sucrose gradients, gel filtration, and negative-stain EM (oligomer); Bscl2−/− MEF differentiation with pharmacological lipolysis rescue (adipogenesis)

    PMID:21062080 PMID:22269949

    Open questions at the time
    • How seipin restrains cAMP/PKA signaling molecularly unresolved
    • Whether oligomer stoichiometry is fixed or dynamic unclear
  6. 2012 High

    Seipin was identified as a regulated adaptor for lipin 1 at the ER membrane during adipogenesis; seipin loss decreased lipin 1 membrane association and elevated phosphatidic acid, placing seipin in the glycerolipid biosynthetic pathway.

    Evidence Co-immunoprecipitation, PA measurement, and lipin 1 membrane fractionation in differentiating adipocytes; mutant seipin unable to bind lipin 1 fails to reduce PA

    PMID:24024128

    Open questions at the time
    • Whether PA accumulation is the proximal cause of differentiation failure or a secondary effect unknown
    • Structural basis of seipin–lipin 1 interaction unresolved
  7. 2015 High

    Atomic force microscopy demonstrated that seipin dodecamers simultaneously bind AGPAT2 and lipin 1, establishing seipin as a physical scaffold organizing consecutive glycerolipid biosynthetic enzymes.

    Evidence AFM imaging of direct protein–protein association and co-immunoprecipitation of ternary complex

    PMID:25737955

    Open questions at the time
    • Stoichiometry of AGPAT2 and lipin 1 within the dodecameric complex not determined
    • Whether scaffolding alters enzyme kinetics not tested
  8. 2016 High

    Seipin was shown to physically interact with and regulate GPAT3 activity; GPAT overexpression phenocopied seipin loss, while GPAT3 knockdown partially rescued seipin-deficient adipogenesis, extending the enzyme scaffold to three consecutive glycerolipid pathway steps. Separately, seipin was shown to maintain stable ER–LD contacts, with its absence causing loss of contacts, increased LD mobility, and defective protein/lipid cargo delivery to LDs.

    Evidence Co-IP, GPAT kinetics, multi-organism epistasis (yeast/fly/mammalian); live-cell imaging, electron tomography, and patient-cell LD tracking

    PMID:27806294 PMID:27879284

    Open questions at the time
    • How seipin modulates GPAT catalytic rate mechanistically unclear
    • Whether ER–LD contact stabilization and enzyme scaffolding are separable functions not tested
  9. 2018 High

    Cryo-EM structures of human (undecamer) and Drosophila (dodecamer) seipin revealed lumenal β-sandwich folds with structural similarity to lipid-binding proteins and hydrophobic helices positioned within the bilayer; the lumenal domain binds anionic phospholipids including PA. In parallel, Drosophila studies linked seipin to ER calcium homeostasis via SERCA, with downstream effects on mitochondrial calcium import and TCA-cycle-dependent lipogenesis.

    Evidence Cryo-EM at ~3.8–4.0 Å with lipid-binding assays and functional mutagenesis; Drosophila metabolomics with calcium measurements and citrate rescue

    PMID:30049710 PMID:30293840 PMID:30327422

    Open questions at the time
    • Atomic-resolution lipid-binding pose within the lumenal domain not resolved
    • Whether the calcium-homeostasis function is structurally separable from the LD-biogenesis function unknown
  10. 2019 High

    LDAF1/TMEM159 was identified as a stoichiometric seipin partner that co-purifies with TAG; LDs form at LDAF1–seipin complexes, and LDAF1 dissociates to the LD surface after budding. Seipin was also shown to mediate uniform ER–LD necks that prevent Ostwald ripening, and its relocalization redirects LD formation sites. Additionally, ATGL was placed downstream of seipin: genetic or pharmacological ATGL inhibition rescued lipodystrophy in Bscl2−/− mice.

    Evidence Co-purification with TAG, LDAF1 relocalization assay, auxin-inducible seipin degron, model membranes, ATGL KO rescue of Bscl2−/− mice

    PMID:31178403 PMID:31185001 PMID:31708432

    Open questions at the time
    • Structural basis of LDAF1 engagement within the seipin ring unresolved
    • Mechanism by which seipin regulates ATGL protein stability unknown
  11. 2021 High

    Molecular dynamics and the yeast Sei1/Ldb16 cryo-EM structure revealed that seipin concentrates TAG and DAG inside its ring via polar/hydroxyl residues in transmembrane and partner subunits, providing a molecular explanation for neutral lipid nucleation.

    Evidence Coarse-grained and all-atom MD simulations with mutagenesis; cryo-EM of Sei1/Ldb16 complex plus biochemical reconstitution

    PMID:33674387 PMID:34625558

    Open questions at the time
    • Direct experimental visualization of lipid within the ring at atomic resolution lacking
    • How opening of the cage permits LD budding in real time not observed
  12. 2022 High

    Yeast seipin cryo-EM revealed a decameric cage with two alternating TM conformations regulated by switch regions; functional mutagenesis showed switch regions are essential, supporting a model in which conformational switching enables TAG phase separation then LD budding. Mammalian studies confirmed seipin at MAMs facilitates mitochondrial calcium import, sustaining Krebs cycle metabolites and ATP.

    Evidence Cryo-EM structure with switch-region mutagenesis; proximity ligation, live calcium imaging, and metabolomics upon acute seipin removal in adipocytes

    PMID:35021082 PMID:35210614 PMID:35938957

    Open questions at the time
    • Conformational transition between open and closed states not captured in time-resolved experiments
    • Whether the MAM-localized pool of seipin is structurally distinct from ER–LD pool unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how seipin's LD-biogenesis and ER–mitochondria contact functions are structurally partitioned, the atomic mechanism by which seipin cage opening permits LD budding, and how seipin restrains cAMP/PKA lipolytic signaling at the molecular level.
  • No time-resolved structural data capturing cage conformational dynamics
  • Molecular link between seipin and cAMP/PKA pathway components unidentified
  • Whether LDAF1 occupies a defined site within the seipin ring structurally unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 4 GO:0008289 lipid binding 4 GO:0060090 molecular adaptor activity 4
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005811 lipid droplet 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 2
Partners
AGPAT2CANXGPAT3LPIN1PLIN2TMEM159YWHAB
Complex memberships
Seipin oligomeric ring (9-12mer)Seipin-LDAF1 complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Seipin localizes to the endoplasmic reticulum and concentrates at ER-lipid droplet junctions; its absence in yeast results in irregular and clustered lipid droplets with proliferated ER, and human seipin can functionally replace yeast seipin (but lipodystrophy-causing missense mutations cannot), establishing seipin's role in lipid droplet morphology and maintenance. Yeast genetic screen, fluorescence microscopy of seipin-GFP, complementation assay with human seipin, fibroblast analysis from BSCL2 patient Proceedings of the National Academy of Sciences of the United States of America High 18093937
2006 Seipin is an integral ER membrane protein with an N-cytoplasm/C-cytoplasm topology and a long luminal loop between two transmembrane helices; this topology was established by in vitro topology mapping assay. In vitro topology mapping assay FEBS letters High 16574104
2004 Heterozygous N88S and S90L missense mutations in BSCL2 disrupt N-glycosylation of seipin and cause aggregate formation in the ER, linking aberrant glycosylation and protein aggregation to dominantly inherited motor neuropathy (dHMN/Silver syndrome). Direct sequencing, expression of mutant constructs in cells, glycosylation assay, immunofluorescence detection of aggregates Nature genetics High 14981520
2008 Seipin is essential for adipocyte differentiation in a cell-autonomous manner; its knockdown in mesenchymal stem cells impairs sustained expression of PPARγ and C/EBPα and persistently reduces expression of triglyceride synthesis genes (AGPAT2, lipin 1, DGAT2), blocking lipid accumulation. A pathogenic missense mutant (A212P) shows aberrant subcellular targeting. shRNA knockdown in C3H10T1/2 cells, qRT-PCR, immunofluorescence of mutant localization Diabetes High 18458148
2008 Yeast seipin (Fld1p/YLR404W) regulates lipid droplet size; its deletion causes supersized LDs with enhanced fusion activity both in vivo and in vitro, and lipid profiling reveals altered acyl chain compositions of major phospholipids in fld1Δ cells. Human seipin rescues these defects. Yeast genetic screen (~4700 mutants), fluorescence microscopy, in vitro and in vivo LD fusion assay, lipidomics, cross-species complementation The Journal of cell biology High 18250201
2010 Seipin forms a discrete homo-oligomeric complex of ~9 copies (~500 kDa) in the ER and appears as a toroid by negative-stain EM; the A212P lipodystrophy allele forms only smaller, unstable complexes, suggesting oligomer integrity is required for function. Affinity purification, detergent sucrose gradients (H2O and D2O), gel filtration, negative-stain electron microscopy Biochemistry High 21062080
2007 N88S and S90L mutant seipin is polyubiquitinated, degraded via ER-associated degradation (ERAD), stably binds the ER chaperone calnexin (indicating unfolded protein accumulation), and triggers ER stress-mediated apoptosis in neuronal cells, establishing that seipinopathies are conformational diseases linked to ER stress. Co-immunoprecipitation (seipin–calnexin), ubiquitination assay, proteasome inhibitor treatment, ER stress marker measurements, apoptosis assay Annals of neurology High 17387721
2011 Absence of Bscl2 in mouse embryonic fibroblasts and stromal vascular cells causes normal early adipocyte differentiation but failure of terminal differentiation due to unrestrained cAMP/PKA-activated lipolysis, leading to loss of lipid droplets and silencing of adipose-specific transcription factors; this defect is rescued by lipolysis inhibitors but not by PPARγ agonist alone. Bscl2−/− mouse model, in vitro MEF/SVC differentiation, lipolysis inhibitor rescue experiments, gene expression analysis Molecular and cellular biology High 22269949
2012 Seipin acts as an ER membrane adaptor that inducibly binds the phosphatidic acid (PA) phosphatase lipin 1 during adipogenesis; seipin knockdown decreases lipin 1 membrane association and increases PA accumulation, while wild-type but not a lipin-1-binding-deficient mutant of seipin reduces PA levels in differentiating cells. Co-immunoprecipitation, PA measurement, lipin 1 membrane fractionation, seipin overexpression/mutant expression in differentiating adipocytes Molecular metabolism High 24024128
2015 Seipin dodecamers can directly and simultaneously bind both AGPAT2 and lipin 1, physically scaffolding these two consecutive enzymes of the PA biosynthetic/catabolic pathway; atomic force microscopy demonstrates direct protein–protein association and defines the molecular architecture of the complex. Co-immunoprecipitation, atomic force microscopy (direct binding), immunofluorescence Molecular metabolism High 25737955
2013 Seipin interacts with 14-3-3β through its N- and C-termini; 14-3-3β recruits cofilin-1 to remodel actin cytoskeleton from stress fibers to cortical structures during adipogenesis, and knockdown of cofilin-1, 14-3-3β, or seipin impairs adipocyte development with retention of stress fibers. Co-immunoprecipitation, fluorescence microscopy of actin structures, shRNA knockdown in 3T3-L1 cells, severing-resistant actin mutant expression Human molecular genetics Medium 24026679
2016 Seipin physically interacts with microsomal glycerol-3-phosphate acyltransferase (GPAT) isoforms; SEIPIN-deficient cells and tissues show elevated GPAT activity and altered GPAT kinetics, and GPAT overexpression phenocopies seipin loss (supersized LDs, blocked adipogenesis) while GPAT3 knockdown partially rescues adipogenesis in seipin-deficient preadipocytes. Co-immunoprecipitation, GPAT activity assay (kinetics), genetic overexpression/knockdown across yeast/fly/mammalian systems, pharmacological GPAT inhibition in Seipin−/− preadipocytes Cell reports High 27806294
2016 Seipin is stably associated with nascent ER-LD contacts (typically one focal point per LD) in human cells; seipin knockout or patient (BSCL2) cells completely lack or have aberrant ER-LD contacts, leading to increased LD mobility, impaired protein delivery from ER to LDs, and defective fatty acid incorporation into neutral lipids in cells with pre-existing LDs. Live-cell fluorescence microscopy, electron tomography, seipin KO and patient cell lines, LD mobility tracking, lipid/protein cargo delivery assays The EMBO journal High 27879284
2018 Cryo-EM structure of human SEIPIN at 3.8 Å reveals an undecameric ring; the lumenal domain forms an eight-stranded β-sandwich fold. Both full-length SEIPIN and its lumenal domain bind anionic phospholipids including phosphatidic acid, suggesting seipin maintains phospholipid homeostasis and ER surface tension. Cryo-electron microscopy (3.8 Å structure), lipid-binding assay (phospholipid binding to full-length and lumenal domain) Developmental cell High 30293840
2018 Cryo-EM structure of Drosophila seipin reveals a ring-shaped dodecamer; each monomer has a hydrophobic helix (HH) positioned toward the ER bilayer and a β-sandwich domain with structural similarity to lipid-binding proteins. Functional testing in cells supports a model in which seipin HHs detect forming LDs and then act as membrane anchors enabling lipid transfer and LD growth. Cryo-electron microscopy (~4.0 Å), cell-based functional assays of HH mutants The Journal of cell biology High 30327422
2019 LDAF1 (TMEM159) is a direct interaction partner of seipin; together they form an ~600 kDa oligomeric complex that co-purifies with triacylglycerol. LDs form at LDAF1-seipin complexes, and relocalization of LDAF1 to the plasma membrane co-recruits seipin and redirects LD formation. After LD formation, LDAF1 dissociates from seipin and moves to the LD surface. Without LDAF1, LDs only form at significantly higher TG concentrations. Co-immunoprecipitation, mass spectrometry, TG co-purification, live-cell imaging of LDAF1/seipin relocalization, TG concentration assays Developmental cell High 31708432
2019 Seipin mediates uniform ER-LD neck contacts that facilitate triglyceride flow from the ER to LDs; without seipin, LDs become heterogeneous in size via a biophysical ripening (Ostwald ripening) process where TG partitions from smaller to larger LDs through droplet-bilayer contacts. Relocalizing seipin to the nuclear envelope redirects LD formation to seipin-defined sites. Seipin relocalization to nuclear envelope, acute seipin removal (auxin-inducible degron), live-cell imaging, electron tomography, model membrane experiments, coarse-grained simulations Developmental cell High 31178403
2021 Molecular dynamics simulations show that seipin clusters triacylglycerol and diacylglycerol inside its ring-like oligomeric structure via interactions involving both luminal and transmembrane regions; polar residues responsible for TG interactions are identified, and mutations of these to hydrophobic residues abolish TG clustering. Molecular dynamics simulations (coarse-grained and all-atom), mutagenesis of polar residues Proceedings of the National Academy of Sciences of the United States of America Medium 33674387
2022 Cryo-EM structure of S. cerevisiae seipin reveals a decameric cage; lumenal domains form a stable ring and transmembrane segments form cage sides/top with two alternating conformations regulated by switch regions. Switch region mutations abolish seipin function. A model is proposed in which the closed cage enables TG phase separation and an open conformation allows LD budding. Cryo-electron microscopy plus structural modeling, functional mutagenesis of switch regions in cells Nature structural & molecular biology High 35210614
2022 All-atom MD simulations show that seipin TM segment residues and hydrophobic helix residues (in the phospholipid tail region) attract TG, and coarse-grained models show TM segments form a constricted neck to facilitate conversion of a flat oil lens into a budding LD. Conserved positively charged residues at TM segment ends affect LD maturation in cell experiments. Molecular dynamics simulations (all-atom and coarse-grained), cell-based experiments with TM charge mutants eLife Medium 35583926
2021 Structural and biochemical analysis of yeast Sei1/Ldb16 complex shows that Sei1 luminal domain assembles a homooligomeric ring but cannot itself concentrate TG; instead, Sei1 positions Ldb16, which concentrates TG within the Sei1 ring via critical hydroxyl residues. Sei1 TM segments also promote TG recruitment and control Ldb16 stability. Cryo-EM structure, biochemical assays, molecular dynamics simulations, mutagenesis of Ldb16 hydroxyl residues Nature communications High 34625558
2022 Yeast Seipin (Sei1/Ldb16) promotes storage of diverse neutral lipids (TAG, steryl esters, retinyl esters) in LDs; human seipin restores normal SE-containing LDs in yeast seipin mutants. The mechanism involves interactions between hydroxyl residues in human seipin or yeast Ldb16 with neutral lipid carboxyl esters. Yeast genetics, complementation with human seipin, mutagenesis of hydroxyl residues, neutral lipid profiling The Journal of cell biology High 35938957
2018 In Drosophila, Seipin promotes ER calcium homeostasis through SERCA; loss of dSeipin impairs mitochondrial TCA cycle activity and reduces citrate levels (required for lipogenesis) by reducing mitochondrial calcium import. Lipid storage defects in dSeipin mutant fat cells can be rescued by restoring mitochondrial calcium or citrate. Drosophila genetics, metabolomics, calcium measurement, genetic rescue with citrate supplementation The EMBO journal High 30049710
2022 A subset of seipin localizes to ER-mitochondria contact sites (MAMs) in human and mouse adipocytes, in the vicinity of calcium regulators SERCA2, IP3R, and VDAC; acute seipin removal leads to defective mitochondrial calcium import, widespread reduction in Krebs cycle metabolites, and decreased ATP levels without altering ER calcium stores. Proximity ligation assay, subcellular fractionation, live-cell calcium imaging, metabolomics, acute seipin deletion (inducible), proximity to MAM calcium regulators Cell reports High 35021082
2015 In yeast, absence of seipin leads to localized accumulation of phosphatidic acid (PA puncta) at ER-LD junctions detected by three independent probes; this PA accumulation requires the first 14 amino acids (N-terminus) of Sei1p, and suppression of PA puncta requires functional cooperation between Sei1p N-terminus and Ldb16p. Yeast genetics, multiple PA probes (Opi1p, Spo20p, Pah1p), deletion/complementation analysis BMC cell biology Medium 26637296
2019 Yeast seipin negatively regulates sphingolipid production by associating with serine palmitoyltransferase (SPT) and fatty acid elongase at ER-LD contacts; cells lacking seipin show elevated SPT and FA elongase activities and accumulate sphingoid precursors/intermediates. Human seipin rescues altered sphingolipid levels in yeast seipin mutants. Co-immunoprecipitation of seipin with SPT and FA elongase, sphingolipid enzyme activity assays, lipidomics, yeast genetics, cross-species complementation The Journal of cell biology Medium 31594806
2018 In yeast, seipin cooperates with the membrane-shaping protein Pex30 to facilitate organelle budding (both lipid droplets and peroxisomes) from the ER; absence of both leads to ER accumulation of TG and peroxisomal membrane proteins without affecting COPII vesicle formation, and this can be reversed by remodeling ER phospholipid composition. Yeast genetics (double deletion), electron microscopy, lipid composition analysis, organelle fractionation Nature communications High 30054465
2011 Drosophila dSeipin loss causes ectopic lipid droplet accumulation in a tissue-autonomous manner in the salivary gland; dSeipin mutants show synergistic genetic interactions with lipogenic genes, and the phenotype is consistent with seipin participating in phosphatidic acid metabolism to down-regulate lipogenesis. Drosophila genetics, tissue-specific rescue, genetic epistasis with lipogenic genes, lipid droplet imaging PLoS genetics Medium 21533227
2011 Seipin functions as a scaffolding protein in the ER; deletion of FLD1 (yeast seipin) leads to impaired lipid droplet dynamics and defective lipolysis associated with aberrant ER structures, consistent with seipin organizing a specific ER subdomain. 4D live-cell imaging, transmission electron microscopy, electron tomography, quantitative microscopy in S. cerevisiae Journal of cell science Medium 22100922
2013 Wild-type human seipin forms dodecamers (12 subunits in a circular configuration) as shown by atomic force microscopy; the L91P and A212P lipodystrophy mutants fail to form this 12-mer structure, and several mutants (R275X, frameshift) fail to bind lipin 1 appropriately. Atomic force microscopy, co-immunoprecipitation (seipin–lipin 1 interaction), expression analysis of mutant constructs Diabetologia High 23989774
2008 The transmembrane domains of seipin are critical for its ER retention, ubiquitination, formation of inclusion bodies, and activation of the unfolded protein response (UPR); seipin is expressed in neurons of the spinal cord and frontal cortex. Deletion/domain mutagenesis of seipin constructs, ubiquitination assay, UPR marker measurements, immunohistochemistry Neurobiology of disease Medium 18585921
2011 Seipin knockdown in mammalian cells increases oleate incorporation into TAG and steady-state TAG levels, and induces proliferation and clustering of small LDs; overexpression reduces TAG synthesis and LD formation. The N88S/S90L neuropathy mutants dominantly cause small LD clustering by trapping wild-type seipin in inclusions; seipin can interact with itself and its mutant forms. shRNA knockdown, seipin overexpression, lipid incorporation assay (oleate-TAG), co-immunoprecipitation (seipin self-interaction), fluorescence microscopy Journal of lipid research Medium 21957196
2009 Seipin deficiency in lymphoblastoid cells from BSCL patients (null BSCL2 mutations) alters lipid droplet morphology (decreased size, increased number) and causes a defect in fatty acid Δ9-desaturation, with increased saturated fatty acids in TG and phosphatidylethanolamine, suggesting seipin acts at a proximal step linking Δ9-desaturase activity to lipid droplet formation. Lipid profiling of patient lymphoblastoid cells, fatty acid composition analysis by GC, fluorescence microscopy of LDs Biochimie Medium 19278620
2012 Seipin regulates excitatory synaptic transmission in cortical neurons via a post-synaptic mechanism; seipin knockdown reduces AMPA receptor surface levels and AMPA-induced currents without altering inhibitory post-synaptic currents or pre-synaptic ultrastructure. These defects are rescued by expression of shRNA-resistant human seipin. shRNA knockdown in cultured neurons, whole-cell patch-clamp electrophysiology, AMPA/IPSC recording, surface AMPA receptor immunostaining and biochemistry Journal of neurochemistry Medium 23173741
2016 Neuronal seipin deficiency causes selective reduction of AMPA receptor expression in hippocampal CA1 pyramidal neurons via decreased ERK-CREB phosphorylation and reduced PPARγ, leading to impaired LTP and spatial memory deficits; PPARγ agonist rosiglitazone rescues AMPAR expression and LTP through ERK-CREB pathway. Neuronal seipin-knockout mice, Morris water maze, LTP recording (hippocampal slices), whole-cell patch-clamp, AMPAR immunostaining, MEK inhibitor experiments The Journal of neuroscience Medium 26818512
2016 BSCL2 deletion specifically in brown adipocyte progenitors in mice causes unrestrained cAMP/PKA-mediated lipolysis and premature metabolic activation of differentiating brown adipocytes, ultimately resulting in BAT atrophy via apoptosis; BSCL2 is not required for the core brown adipogenic transcriptional program. Brown adipocyte-specific Bscl2 knockout mice, BAT morphology/function analysis, cAMP/PKA pathway measurement, apoptosis assays, gene expression profiling Molecular and cellular biology High 27185876
2019 Bscl2−/− hearts exhibit increased ATGL protein stability and expression, causing drastic reduction of glycerolipids and excessive fatty acid oxidation; pharmacological or genetic inhibition of ATGL rescues adipocyte differentiation and lipodystrophy in Bscl2−/− cells and mice, placing BSCL2 upstream of ATGL in regulating adipocyte lipid storage. Bscl2−/− mouse model, ATGL inhibitor/genetic deletion rescue, lipidomics, cardiac function measurement, hyperinsulinemic-euglycemic clamp JCI insight High 31185001
2016 BSCL2/Seipin knockdown in hepatocytes increases LD number and size and induces SCD1 expression and activity; SCD1 knockdown reverses the LD phenotype associated with Seipin deficiency, placing SCD1 downstream of Seipin in regulating hepatic LD homeostasis. siRNA knockdown in primary and cultured hepatocytes, LD imaging, SCD1 activity assay, double knockdown epistasis Lipids Medium 27838812
2016 SEIPIN interacts with ADRP (adipose differentiation-related protein/perilipin 2) as shown by co-immunoprecipitation; seipin defines ADRP's punctate cytoplasmic localization, and restoration of BSCL2 in patient-derived iPSCs rescues both lipid droplet formation and cytoplasmic punctate ADRP localization. Co-immunoprecipitation, iPSC differentiation model from BSCL2-null patients, rescue with wild-type BSCL2, fluorescence microscopy Metabolism: clinical and experimental Medium 26975546
2020 Seipin and GPAT3 associate via direct protein-protein interaction; seipin can simultaneously bind GPAT3 and AGPAT2 in the same complex; loss of GPAT3 in seipin-deficient preadipocytes exacerbates adipogenic failure, indicating GPAT3 has a modest positive role in adipogenesis within the seipin-regulated pathway. Co-immunoprecipitation, siRNA knockdown, adipocyte differentiation assays Scientific reports Medium 32094408
2019 Promethin (TMEM159/LDAF1) is a seipin partner protein that forms a complex with seipin; promethin localizes to LD surfaces, and its LD targeting is modulated by seipin expression levels. Co-immunoprecipitation, fluorescence microscopy, modulation of seipin expression levels Cells Medium 30901948

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proceedings of the National Academy of Sciences of the United States of America 503 18093937
2008 Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. The Journal of cell biology 402 18250201
2004 Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nature genetics 305 14981520
2016 Seipin regulates ER-lipid droplet contacts and cargo delivery. The EMBO journal 251 27879284
2019 LDAF1 and Seipin Form a Lipid Droplet Assembly Complex. Developmental cell 177 31708432
2018 Human SEIPIN Binds Anionic Phospholipids. Developmental cell 167 30293840
2008 The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation. Diabetes 167 18458148
2019 Seipin Facilitates Triglyceride Flow to Lipid Droplet and Counteracts Droplet Ripening via Endoplasmic Reticulum Contact. Developmental cell 165 31178403
2011 Seipin ablation in mice results in severe generalized lipodystrophy. Human molecular genetics 150 21551454
2018 Cryo-electron microscopy structure of the lipid droplet-formation protein seipin. The Journal of cell biology 142 30327422
2012 Berardinelli-seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation. Molecular and cellular biology 140 22269949
2015 Arabidopsis SEIPIN Proteins Modulate Triacylglycerol Accumulation and Influence Lipid Droplet Proliferation. The Plant cell 137 26362606
2016 SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase. Cell reports 136 27806294
2011 Tissue-autonomous function of Drosophila seipin in preventing ectopic lipid droplet formation. PLoS genetics 124 21533227
2018 Seipin and the membrane-shaping protein Pex30 cooperate in organelle budding from the endoplasmic reticulum. Nature communications 119 30054465
2003 Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes. The Journal of clinical endocrinology and metabolism 114 14602785
2009 The human lipodystrophy gene product Berardinelli-Seip congenital lipodystrophy 2/seipin plays a key role in adipocyte differentiation. Endocrinology 113 19574402
2011 A role for seipin in lipid droplet dynamics and inheritance in yeast. Journal of cell science 110 22100922
2009 Seipin deficiency alters fatty acid Delta9 desaturation and lipid droplet formation in Berardinelli-Seip congenital lipodystrophy. Biochimie 108 19278620
2012 Seipin: from human disease to molecular mechanism. Journal of lipid research 105 22474068
2010 Seipin is a discrete homooligomer. Biochemistry 105 21062080
2017 Identification of seipin-linked factors that act as determinants of a lipid droplet subpopulation. The Journal of cell biology 104 29187527
2006 Membrane topology of the human seipin protein. FEBS letters 104 16574104
2014 Adipose-specific knockout of SEIPIN/BSCL2 results in progressive lipodystrophy. Diabetes 92 24622797
2011 Seipin, adipogenesis and lipid droplets. Trends in endocrinology and metabolism: TEM 89 21497513
2021 Seipin accumulates and traps diacylglycerols and triglycerides in its ring-like structure. Proceedings of the National Academy of Sciences of the United States of America 82 33674387
2022 Seipin forms a flexible cage at lipid droplet formation sites. Nature structural & molecular biology 81 35210614
2004 The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain : a journal of neurology 81 15242882
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