Affinage

STARD3

StAR-related lipid transfer protein 3 · UniProt Q14849

Length
445 aa
Mass
50.5 kDa
Annotated
2026-06-10
56 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STARD3 (MLN64) is a late endosomal transmembrane sterol-transfer protein that mobilizes cholesterol from late endosomes/lysosomes to mitochondria and the ER, coupling endosomal lipid handling to steroidogenesis, organelle dynamics, and membrane contact site formation (PMID:12070139, PMID:19965586, PMID:28377464). Its modular architecture separates targeting from transfer: an N-terminal MENTAL/transmembrane domain anchors the protein to the limiting membrane of late endosomes, mediates homo- and hetero-dimerization (including with MENTHO), and binds cholesterol, while the C-terminal START domain projects into the cytoplasm and shuttles single cholesterol molecules to acceptor membranes (PMID:11053434, PMID:12393907, PMID:16709157). The START domain is necessary and sufficient for StAR-like steroidogenic activity, stimulating cholesterol transfer to the inner mitochondrial membrane and between phospholipid vesicles as a pH-dependent molten globule, and is proteolytically liberated as an N-218/28-kDa fragment that drives placental steroid synthesis (PMID:9237999, PMID:10995240, PMID:14715710, PMID:25459514). This NPC1-independent endosome-to-mitochondria cholesterol route, and the resulting mitochondrial cholesterol loading, governs steroidogenesis but also drives mitochondrial dysfunction—membrane hyperpolarization, ROS, and GSH depletion—when overactive (PMID:19965586, PMID:28282615, PMID:23028046). STARD3 builds the membrane contact sites underlying this transport: it tethers late endosomes to the ER by binding ER-resident VAP-A/VAP-B through a Phospho-FFAT motif, an interaction switched on by GSK3α/β phosphorylation of Ser209, and reconstitution shows STARD3–VAP assemble an efficient ER-to-endosome cholesterol-transport machine (PMID:27068960, PMID:28377464, PMID:41741634). STARD3 likewise organizes late endosome–mitochondria contacts and actin/Arp2/3-dependent late endosome dynamics, both dependent on its cholesterol-binding activity (PMID:15930133, PMID:37245582). Beyond cholesterol, STARD3 is the retinal lutein-binding protein, selectively binding lutein over zeaxanthin via its helix-grip START fold (PMID:21322544, PMID:27487925), and undergoes a protective methionine-oxidation/MSR-reduction cycle that detoxifies cholesterol hydroperoxides during transport (PMID:37507014).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 High

    Established that STARD3 has a modular two-domain organization, defining the C-terminal START domain as the steroidogenic effector and the N-terminal region as the localization determinant.

    Evidence Deletion/truncation mutants co-expressed with cholesterol side-chain cleavage system and localized by immunofluorescence

    PMID:9139840 PMID:9237999

    Open questions at the time
    • Did not identify the precise organelle of localization
    • Mechanism of cholesterol transfer not resolved
  2. 2000 High

    Pinpointed the late endosomal limiting membrane as STARD3's residence and showed the isolated START domain acts as a molten globule transferring cholesterol to mitochondria, resolving how the domains divide labor.

    Evidence EM/IF localization with targeting-motif mutagenesis; bacterially expressed N-218 fragment in isolated mitochondria steroidogenesis and CD spectroscopy

    PMID:10995240 PMID:11053434 PMID:11196440

    Open questions at the time
    • Did not establish physiological cleavage in non-placental tissues
    • Acceptor specificity beyond mitochondria unaddressed
  3. 2002 High

    Defined the MENTAL domain as the dimerization/cholesterol-binding/endosome-targeting module and showed the START domain mobilizes lysosomal cholesterol, linking sterol transfer to late endocytic function.

    Evidence GFP trafficking, in vitro mitochondrial transfer assay, ΔStart dominant-negative overexpression, and MENTHO interaction/cholesterol-binding assays

    PMID:12070139 PMID:12393907

    Open questions at the time
    • Native heterodimer stoichiometry unknown
    • How MENTAL-bound cholesterol is handed to START not defined
  4. 2004 High

    Quantified START-domain cholesterol transfer kinetics and tested physiological requirement in vivo, revealing only cell-type-specific steroidogenic dependence rather than global sterol disruption.

    Evidence In vitro vesicle/mitochondria transfer assays; targeted START-domain mouse mutant with lipid and steroidogenesis phenotyping; hepatocyte overexpression

    PMID:14715710 PMID:14963026 PMID:15342684

    Open questions at the time
    • Redundancy with other sterol transporters not resolved
    • Full knockout not characterized in this corpus
  5. 2005 High

    Connected STARD3 sterol transfer to actin-dependent late endosome positioning and fusion, showing the cholesterol-binding function controls organelle dynamics.

    Evidence siRNA and overexpression with live imaging, actin/p34-Arc staining, and rescue with cholesterol-binding-deficient mutants

    PMID:15930133

    Open questions at the time
    • Direct link between sterol level and Arp2/3 recruitment not mechanistically defined
    • Single lab
  6. 2008 Medium

    Demonstrated that the STARD3 START domain binds cholesterol by a mechanism distinct from STARD1, refining the structural basis of sterol recognition.

    Evidence Trypsin protection and photoaffinity labeling comparing STARD3-START and STARD1-START

    PMID:18331352

    Open questions at the time
    • High-resolution cholesterol-bound structure not determined here
    • Functional consequence of differential binding unclear
  7. 2009 High

    Established STARD3 as required for an NPC1-independent endosome-to-mitochondria cholesterol route, placing it in a parallel pathway to canonical lysosomal cholesterol egress.

    Evidence siRNA in NPC1-deficient CHO cells with pregnenolone and mitochondrial cholesterol measurement

    PMID:19965586

    Open questions at the time
    • Direct LE-mitochondria transfer mechanism not visualized here
    • Contribution relative to NPC1 pathway in vivo unquantified
  8. 2011 High

    Identified STARD3 as the macular lutein-binding protein, extending its ligand repertoire beyond cholesterol.

    Evidence Surface plasmon resonance with recombinant STARD3 and retinal immunohistochemistry

    PMID:21322544

    Open questions at the time
    • Physiological role of lutein binding in retina not established
    • Whether lutein and cholesterol binding compete unknown
  9. 2012 Medium

    Identified regulatory and stress-responsive control of STARD3 trafficking and mitochondrial translocation, showing its localization is actively governed.

    Evidence 14-3-3 interaction by MS/Co-IP and mutagenesis; LeTx/caspase-1-induced mitochondrial translocation with organelle readouts

    PMID:22514632 PMID:23028046

    Open questions at the time
    • 14-3-3 binding site not structurally defined
    • Signaling upstream of mitochondrial translocation incompletely mapped
  10. 2013 Medium

    Resolved STARD3 into a distinct late endosome subpopulation that contacts NPC1/ORP1L compartments, organizing endosomal cholesterol handling spatially.

    Evidence Live-cell imaging and colocalization tracking of MLN64/ABCA3 versus ORP1L/NPC1 endosomes

    PMID:23709693

    Open questions at the time
    • Molecular basis of subpopulation segregation unknown
    • Functional cargo exchange between compartments not measured
  11. 2014 Medium

    Showed mitochondrial metalloprotease cleavage generates an active STARD3 fragment required for placental steroidogenesis, defining proteolytic activation.

    Evidence Isolated syncytiotrophoblast mitochondria, protease inhibitor, and progesterone assays

    PMID:25459514

    Open questions at the time
    • Identity of the responsible metalloprotease unresolved
    • In vivo relevance of cleavage outside placenta unclear
  12. 2016 High

    Determined the helix-grip structure of the START fold and demonstrated direct VAP-dependent ER-endosome tethering, establishing the structural and contact-site machinery.

    Evidence 1.74 Å crystal structure with lutein docking; Co-IP and colocalization of STARD3/STARD3NL with VAP-A/VAP-B

    PMID:27068960 PMID:27487925

    Open questions at the time
    • Cholesterol-bound structure not solved
    • FFAT motif and phospho-regulation not yet defined here
  13. 2017 High

    Reconstituted STARD3–VAP as an ER-to-endosome cholesterol-transport machine requiring both lipid transfer and tethering, and linked excess transport to mitochondrial dysfunction.

    Evidence In vitro transport reconstitution with function-separating mutants and in-cell filipin cholesterol mapping; overexpression/knockdown mitochondrial functional assays

    PMID:28282615 PMID:28377464

    Open questions at the time
    • Directionality and regulation of transport in vivo not fully resolved
    • Coupling between contact formation and transfer rate unquantified
  14. 2019 Medium

    Placed STARD3-dependent ER-endosome contacts within a Rab7/AnxA6-controlled rescue pathway for cholesterol export in NPC1 disease, integrating it with contact-site regulators.

    Evidence siRNA epistasis among STARD3, AnxA6, and TBC1D15/Rab7 with EM of contact sites and filipin

    PMID:31664461

    Open questions at the time
    • Mechanism by which Rab7 activation promotes STARD3 contacts unclear
    • Therapeutic relevance untested
  15. 2023 High

    Expanded STARD3's interactome and protective biochemistry, defining LE-mitochondria contacts, a methionine-oxidation/MSR detox cycle, and an HSP90/HER2 stabilizing role.

    Evidence Immuno-electron tomography with STARD3 knockdown; MS mapping of oxidized Met307/Met427 with MSR reduction assays; Co-IP and KD/OE of HER2/phospho-SRC pathway

    PMID:37245582 PMID:37507014 PMID:38058811

    Open questions at the time
    • How LE-mitochondria tethers form molecularly not fully defined
    • STARD3-HSP90-HER2 mechanism is single-lab and indirect
  16. 2024 Medium

    Extended STARD3's contact-site scaffolding and disease relevance, showing it bridges LIMP-2–VAPB at ER-lysosome contacts and drives mitochondrial cholesterol injury in diabetic podocytes.

    Evidence BioID/Co-IP with STARD3-depletion epistasis; diabetic in vivo/in vitro models with filipin and mitochondrial readouts

    PMID:38754814 PMID:39370902

    Open questions at the time
    • Stoichiometry of LIMP-2–STARD3–VAPB complex unknown
    • Causality in disease versus correlation not fully separated
  17. 2026 High

    Identified GSK3α/β phosphorylation of Ser209 as the switch activating STARD3 tethering, and uncovered a second STARD3 function promoting homotypic endosome interactions when tethering is off.

    Evidence Kinase identification, S209 phospho-mutagenesis, GSK3 inhibition, and live-cell imaging of ER-endosome contacts and endosome positioning

    PMID:41741634

    Open questions at the time
    • Upstream signals controlling GSK3 toward STARD3 unknown
    • Physiological trigger toggling between tethering and homotypic function undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How STARD3's multiple roles—cholesterol transfer, lutein binding, contact-site tethering, and oxidative detoxification—are coordinated and prioritized within a single cell remains unresolved.
  • No integrated model of how ligand selection (cholesterol vs lutein) is regulated
  • Tissue-specific functional hierarchy not established
  • In vivo loss-of-function consequences beyond conditional models incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 7 GO:0060090 molecular adaptor activity 3 GO:0140104 molecular carrier activity 3
Localization
GO:0005739 mitochondrion 4 GO:0005768 endosome 4 GO:0005783 endoplasmic reticulum 3 GO:0005764 lysosome 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-5653656 Vesicle-mediated transport 3
Partners
HSP90LIMP-2MENTHOMFN2MSRASTARD3NLVAPAVAPB
Complex memberships
LIMP-2-STARD3-VAPB ER-lysosome contact complexMLN64-MENTHO heterodimerSTARD3-VAP ER-endosome contact tether

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 The C-terminal START/StAR Homology Domain (SHD) of MLN64/STARD3 is necessary and sufficient for steroidogenic activity; deletion of this domain abolishes steroidogenesis, while removal of N-terminal sequences increases it. MLN64 stimulates pregnenolone secretion ~2-fold in COS-1 cells co-transfected with the cholesterol side-chain cleavage enzyme system. COS-1 cell transfection with wild-type and deletion/truncation mutants of MLN64 co-expressed with cholesterol side-chain cleavage enzyme system; pregnenolone secretion assay Proceedings of the National Academy of Sciences of the United States of America High 9237999
1997 The N-terminal transmembrane domain of MLN64/STARD3 is responsible for its specific cytoplasmic (perinuclear, bundle-like) localization; deletion of this domain results in uniform cytoplasmic distribution. Deletion mutagenesis with subcellular localization by immunofluorescence microscopy in transfected cells International journal of cancer Medium 9139840
2000 MLN64/STARD3 localizes exclusively to the limiting membrane of late endosomes via its N-terminal domain, with the START domain projecting into the cytoplasm. A dileucine motif (Leu66-Leu67) and tyrosine residue (Tyr89) in the N-terminal domain are critical for late endosomal targeting or proper folding. MLN64 colocalizes with NPC1 and cholesterol on late endosomes but does not complement NPC2 disease. Immunocytofluorescence, electron microscopy, antibody microinjection/endocytosis, deletion and point mutagenesis of targeting signals, complementation assays The Journal of biological chemistry High 11053434
2000 The truncated N-218 MLN64 protein (lacking 218 N-terminal residues) has StAR-like steroidogenic activity in vitro, stimulating cholesterol transfer from outer to inner mitochondrial membrane. It adopts a molten-globule-like conformation with pH-dependent structural transitions, and its C-terminus is proteolytically accessible while residues 244–414 are resistant, similar to StAR. MLN64 is proteolytically cleaved in the placenta to a size matching N-218 MLN64. Bacterially expressed N-218 MLN64 tested in isolated mitochondria steroidogenesis assay; CD spectroscopy; limited proteolysis + mass spectrometry; Western blot of human placenta Biochemistry High 10995240
2000 Both StAR and N-218 MLN64 act on the outer mitochondrial membrane as molten globules to promote cholesterol transfer; this activity does not require entry into the intramembranous space. Bacterially expressed N-218 MLN64 is active with isolated mitochondria, confirming proper folding. Isolated mitochondria steroidogenesis assay; far-UV CD spectroscopy; urea denaturation; fluorescence spectroscopy; partial proteolysis + mass spectrometry; Western blot Endocrine research Medium 11196440
2002 The N-terminal transmembrane domains of MLN64 mediate its endocytosis from the plasma membrane to late endocytic compartments. The START domain transfers free cholesterol from donor to acceptor mitochondrial membranes and enhances steroidogenesis by placental mitochondria. A dominant-negative ΔStart-MLN64 mutant causes free cholesterol accumulation in lysosomes, inhibits late endocytic dynamics, and suppresses steroidogenesis, demonstrating the START domain's role in lysosomal cholesterol mobilization. GFP-tagged MLN64 trafficking analysis; START domain cholesterol transfer assay with isolated mitochondria; ΔStart dominant-negative overexpression; steroidogenesis assay in COS cells The Journal of biological chemistry High 12070139
2002 MENTHO, an MLN64 N-terminal domain (MENTAL domain) homologue, interacts with MLN64 via the MENTAL domain; both proteins homo- and hetero-dimerize through this domain. The MENTAL domain targets proteins to late endosomal membranes and binds cholesterol in vivo. MENTHO overexpression alters the endocytic compartment, causing accumulation of enlarged endosomes. cDNA cloning; overexpression and subcellular localization; cholesterol-binding assays; interaction studies; endosome morphology analysis The Journal of biological chemistry Medium 12393907
2004 N-218 MLN64 stimulates cholesterol transfer between artificial phospholipid vesicles (initial rate 6.5 mol/min·mol) and to the inner mitochondrial membrane of human placental mitochondria (~6-fold stimulation of pregnenolone synthesis), comparable to N-62 StAR. Both proteins undergo pH-dependent molten globule transitions. MLN64 levels in JEG-3 placental cells are unresponsive to cAMP stimulation. In vitro cholesterol transfer assay with phospholipid vesicles; isolated placental mitochondria steroidogenesis assay; urea denaturation; CD spectroscopy; 8-Br-cAMP stimulation of JEG-3 cells Endocrinology High 14715710
2004 Targeted mutation of the MLN64 START domain in mice causes only modest alterations in sterol metabolism; mice are viable, fertile, and neurologically intact with no major lipid abnormalities. However, embryonic fibroblasts and granulosa cells from mutant mice show reduced conversion of endogenous cholesterol to steroid hormones, indicating a cell-type-specific role of the START domain in sterol trafficking for steroidogenesis. Targeted mouse gene knockout/mutation; plasma lipid analysis; liver lipid distribution; steroidogenesis assay in primary granulosa cells and transfected embryonic fibroblasts The Journal of biological chemistry High 14963026
2004 Overexpression of full-length MLN64 in hepatocytes blunts StAR-, SCP-2-, and CYP7A1-upregulated bile acid synthesis by ~45–48%, suggesting that full-length MLN64 does not deliver cholesterol to mitochondria or ER for CYP27A1/CYP7A1 and may act as a dominant negative in this context. Adenovirus-mediated overexpression of MLN64, StAR, SCP-2, CYP7A1 in primary rat hepatocytes; bile acid synthesis measurement Journal of lipid research Medium 15342684
2005 MLN64 depletion causes dispersion of late endocytic organelles to the cell periphery, decreased actin and Arp2/3 (p34-Arc) association with endosomes, impaired fusion of late endocytic organelles, and delayed cargo degradation. MLN64 overexpression increases actin/p34-Arc-positive patches on late endosomes and enhances fusion in an actin-dependent manner. Cholesterol-binding-deficient MLN64 mutants cannot rescue the dispersion phenotype, linking MLN64-mediated sterol transfer to actin-dependent late endosome dynamics. siRNA knockdown; overexpression; live-cell imaging; immunofluorescence for actin and p34-Arc; cargo degradation assay; rescue experiments with cholesterol-binding mutants Molecular biology of the cell High 15930133
2006 The MENTAL domain mediates MLN64 homo- and hetero-interactions with MENTHO, targets both proteins to late endosomal membranes, and binds cholesterol in vivo; the START domain then shuttles cholesterol to cytoplasmic acceptors. Biochemical characterization; cholesterol-binding assays; subcellular fractionation/localization (review/summary of prior experiments) Biochemical Society transactions Medium 16709157
2008 STARD3-START domain and STARD1-START domain differ in their cholesterol-binding modes: cholesterol stabilizes STARD3-START against trypsin degradation (not STARD1-START); photoaffinity labeling with [3H]azocholestanol labels a specific 6.2 kDa fragment in STARD1-START at the hydrophobic cavity wall, whereas label distributes more equally across STARD3-START polypeptides, indicating differential cholesterol-binding mechanisms. Trypsin protection assay; photoaffinity labeling with [3H]azocholestanol; limited proteolysis The FEBS journal Medium 18331352
2009 MLN64 mediates cholesterol transport from late endosomes to mitochondria independently of NPC1. siRNA knockdown of MLN64 in NPC1-deficient CHO cells decreases cholesterol transport to the inner mitochondrial membrane (measured by pregnenolone production) and reduces mitochondrial cholesterol content, establishing MLN64 as required for an NPC1-independent endosome-to-mitochondria cholesterol transport pathway. RNA interference (siRNA) in NPC1-deficient CHO cells stably expressing CYP11A1 complex; pregnenolone production assay; mitochondrial cholesterol content measurement Journal of lipid research High 19965586
2011 STARD3/MLN64 selectively binds lutein with high affinity (Kd = 0.45 µM) in the primate retina. Recombinant STARD3 binds lutein (but not zeaxanthin) as assessed by surface plasmon resonance, identifying STARD3 as the macular lutein-binding protein. Surface plasmon resonance (SPR) binding assay with recombinant STARD3; Western blotting; immunohistochemistry in monkey retina Biochemistry High 21322544
2012 MLN64 interacts with 14-3-3 proteins at a non-canonical binding site; blocking this interaction (by 14-3-3 antagonist or MLN64 mutagenesis) delays trafficking of MLN64 to the late endosome and disperses endocytic vesicles to the cell periphery, identifying 14-3-3 as a regulator of MLN64 endosomal trafficking. Affinity chromatography and mass spectrometry to identify interacting partners; co-immunoprecipitation in vitro and in vivo; MLN64 mutagenesis; 14-3-3 antagonist treatment; subcellular localization analysis PloS one Medium 22514632
2012 LeTx/caspase-1 signaling triggers mitochondrial translocation of MLN64, causing mitochondrial cholesterol enrichment, membrane hyperpolarization, reactive oxygen species generation, and glutathione depletion. Downregulation of MLN64 in toxin-induced-resistant (TIR) cells (mediated by DNMT1-dependent DNA methylation) prevents these mitochondrial events without blocking caspase-1 activation. Subcellular fractionation; cholesterol measurement; mitochondrial membrane potential assay; ROS measurement; siRNA knockdown; DNA methylation analysis; primary macrophage experiments Molecular and cellular biology Medium 23028046
2013 MLN64/STARD3 and ORP1L define two distinct subpopulations of late endosomes: MLN64-positive LEs contain ABCA3 and receive endocytosed cargo first, cycling between LE and plasma membrane; ORP1L-positive LEs contain NPC1 and are reached later. MLN64/ABCA3 compartments frequently contact ORP1L/NPC1-containing LEs. Fluorescence microscopy; co-localization analysis; live-cell imaging of endocytic cargo trafficking Journal of lipid research Medium 23709693
2014 Mitochondrial metalloproteases cleave STARD3 into a 28-kDa fragment that stimulates progesterone synthesis in isolated human syncytiotrophoblast mitochondria. Metalloprotease inhibitor 1,10-phenanthroline blocks both STARD3 cleavage and steroidogenesis; the 28-kDa fragment stimulates steroidogenesis comparably to truncated STARD3, suggesting proteolytic activation of STARD3 is required for placental cholesterol transport. Isolated syncytiotrophoblast mitochondria; progesterone measurement; Western blot with anti-STARD3; protease inhibitor experiments; 22R-hydroxycholesterol bypass control Biochimica et biophysica acta Medium 25459514
2016 Crystal structure of the lutein-binding domain of human STARD3 refined to 1.74 Å resolution reveals a helix-grip fold around a solvent-filled cavity; rigid-body docking models of lutein indicate one ionone ring must protrude outside the cavity, and steric complementarity involving the ε-ionone ring of lutein may discriminate it from zeaxanthin/meso-zeaxanthin. X-ray crystallography (1.74 Å resolution); rigid-body docking of lutein Acta crystallographica. Section F, Structural biology communications High 27487925
2016 STARD3 and its paralogue STARD3NL tether late endosomes to the ER by directly interacting with ER-resident VAP proteins (VAP-A and VAP-B). Both proteins are anchored on late endosomal limiting membranes and the STARD3–VAP interaction scaffolds ER–endosome contact sites affecting endosome dynamics and cholesterol transport. Co-immunoprecipitation; subcellular fractionation; fluorescence co-localization; functional analysis of ER-endosome contacts (review citing own original data) Biochemical Society transactions Medium 27068960
2017 STARD3 mediates ER-to-endosome cholesterol transport at membrane contact sites. STARD3 induces cholesterol accumulation in endosomes at the expense of the plasma membrane. This transport requires both STARD3's lipid transfer (START domain) activity and its ability to form ER-endosome contacts via interaction with VAP (VAMP-associated protein). In vitro reconstitution demonstrated that STARD3 and VAP assemble into a machine enabling highly efficient cholesterol transport within membrane contacts. In situ cholesterol labeling and quantification; in vitro cholesterol transport reconstitution assay; STARD3 mutants deficient in lipid transfer or VAP interaction; cholesterol distribution analysis by filipin staining The EMBO journal High 28377464
2017 MLN64 overexpression increases mitochondrial cholesterol content and causes mitochondrial dysfunction including decreased GSH, decreased ATPase activity, decreased mitochondrial membrane potential, mitochondrial fragmentation, and increased mitochondrial superoxide. Reduction of MLN64 expression in NPC1-deficient cells restores mitochondrial membrane potential and reduces superoxide levels, confirming MLN64's role in delivering cholesterol to mitochondria. Adenovirus-mediated MLN64 overexpression in mouse liver and hepatocytes; siRNA knockdown in NPC1-deficient cells; mitochondrial membrane potential (JC-1), ROS, GSH, ATPase assays; electron microscopy Redox biology Medium 28282615
2019 In NPC1 mutant cells lacking AnxA6, Rab7 activation promotes ER-endosome membrane contact site formation in a STARD3-dependent manner, enabling late endosome-to-ER cholesterol transfer. Electron microscopy confirmed increased LE-ER MCS in AnxA6-deficient NPC1 cells, and genetic depletion of STARD3 was required for Rab7-mediated rescue of cholesterol export. siRNA knockdown of STARD3 and AnxA6; electron microscopy of MCS; cholesterol distribution (filipin); lipid droplet staining; genetic epistasis between AnxA6, TBC1D15/Rab7, and STARD3 Cellular and molecular life sciences : CMLS Medium 31664461
2022 External cholesterol alters airway epithelial inflammatory sensitivity through a STARD3-MFN2 signaling pathway, causing cholesterol redistribution, altered mitochondrial dynamics, and increased IL production. STARD3 regulation of MFN2 links cholesterol transport to mitochondrial function in bronchial epithelial cells. siRNA knockdown; Western blot; RT-qPCR; mitotracker; Seahorse metabolic assay; lipidomics; electron microscopy Clinical and translational medicine Low 35678098
2023 STARD3 interacts directly with HSP90 and induces phosphorylated SRC signaling, protecting HER2 from lysosomal degradation. STARD3 overexpression increases HER2 protein levels; STARD3 loss leads to HER2 degradation via lysosomes. STARD3 also promotes cell cycle progression by inducing cyclin D1 and reducing p27. Co-immunoprecipitation (STARD3-HSP90); Western blot for HER2, phospho-SRC, cyclin D1, p27; siRNA knockdown; overexpression; lysosomal inhibitor experiments American journal of cancer research Medium 38058811
2023 STARD3 binds all three MSRB isoforms (methionine sulfoxide reductase B) in addition to MSRA; Met307 and Met427 of STARD3 are oxidized by cholesterol-6α-hydroperoxide and cholesterol-7α-hydroperoxide. MSRs reduce these oxidized methionines back to methionine, restoring STARD3 cholesterol-binding activity. This cyclic oxidation-reduction constitutes an efficient mechanism to detoxify cholesterol hydroperoxides during cholesterol transport. Biochemical binding assays; treatment with pure cholesterol hydroperoxide isomers; mass spectrometry of oxidized methionines; MSR-mediated reduction assays; cholesterol-binding activity measurement before/after oxidation The Journal of biological chemistry High 37507014
2023 MLN64 is required for the formation of late endosome–mitochondria membrane contact sites in placental cells. Immuno-electron tomography revealed filamentous tethers connecting late endosomes and mitochondria at <20 nm distance; STARD3 knockdown increased this distance to <150 nm and disrupted tether formation. Perturbation of cholesterol egress from endosomes produced an even longer inter-organelle distance. Immuno-electron microscopy; immuno-electron tomography; STARD3 siRNA knockdown; U18666A treatment; distance measurement of contact sites Experimental cell research High 37245582
2024 LIMP-2 physically interacts with STARD3 and ER-resident VAPB at ER-lysosome contact sites, and STARD3 is required for the LIMP-2–VAPB interaction. Co-immunoprecipitation and imaging confirmed colocalization and physical interaction, suggesting STARD3 scaffolds a LIMP-2–STARD3–VAPB complex at ER-lysosome MCS to facilitate cholesterol transfer. Proximity-based interaction screen (BioID); co-immunoprecipitation; fluorescence colocalization; STARD3 depletion to test LIMP-2/VAPB interaction dependency Journal of cell science Medium 39370902
2024 Upregulation of STARD3 under diabetic/hyperglycemic conditions increases cholesterol transport from late endosomes/lysosomes to mitochondria in podocytes, causing mitochondrial cholesterol accumulation and cell injury. Downregulating STARD3 expression attenuates mitochondrial cholesterol accumulation and improves mitochondrial homeostasis. In vivo and in vitro diabetic models; filipin staining for cholesterol subcellular localization; JC-1 for mitochondrial membrane potential; ROS assay; Western blot; siRNA knockdown Life sciences Medium 38754814
2026 GSK3α and GSK3β phosphorylate serine 209 within the Phospho-FFAT motif of STARD3; this phosphorylation is both necessary and sufficient to activate STARD3's tethering activity, promoting ER–late endosome/lysosome contacts. When ER–LE/Lys tethering is prevented (loss of GSK3-mediated phosphorylation), STARD3 triggers LE/Lys homotypic interactions, revealing a second function in endosome biology. Kinase identification by cell-based and biochemical assays; phospho-site mutagenesis (S209); GSK3 inhibition; live-cell imaging of ER-endosome MCS; endosome positioning analysis The EMBO journal High 41741634

Source papers

Stage 0 corpus · 56 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites. The EMBO journal 215 28377464
1997 MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis. Proceedings of the National Academy of Sciences of the United States of America 215 9237999
2009 MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein. Journal of lipid research 156 19965586
2000 The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein. The Journal of biological chemistry 141 11053434
2011 Identification of StARD3 as a lutein-binding protein in the macula of the primate retina. Biochemistry 138 21322544
2002 MLN64 mediates mobilization of lysosomal cholesterol to steroidogenic mitochondria. The Journal of biological chemistry 130 12070139
1997 MLN64 exhibits homology with the steroidogenic acute regulatory protein (STAR) and is over-expressed in human breast carcinomas. International journal of cancer 121 9139840
2005 Expression of HER2 and the coamplified genes GRB7 and MLN64 in human breast cancer: quantitative real-time reverse transcription-PCR as a diagnostic alternative to immunohistochemistry and fluorescence in situ hybridization. Clinical cancer research : an official journal of the American Association for Cancer Research 88 16322295
2006 Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol. Journal of lipid research 87 16990645
2002 Characterization and expression of steroidogenic acute regulatory protein and MLN64 cDNAs in trout. Endocrinology 85 12021170
2000 N-218 MLN64, a protein with StAR-like steroidogenic activity, is folded and cleaved similarly to StAR. Biochemistry 85 10995240
2013 Cholesterol-binding molecules MLN64 and ORP1L mark distinct late endosomes with transporters ABCA3 and NPC1. Journal of lipid research 82 23709693
2004 Targeted mutation of the MLN64 START domain causes only modest alterations in cellular sterol metabolism. The Journal of biological chemistry 71 14963026
2003 MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein domain. International journal of oncology 71 12739007
2017 MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content. Redox biology 67 28282615
2005 MLN64 is involved in actin-mediated dynamics of late endocytic organelles. Molecular biology of the cell 63 15930133
2019 Annexin A6 modulates TBC1D15/Rab7/StARD3 axis to control endosomal cholesterol export in NPC1 cells. Cellular and molecular life sciences : CMLS 60 31664461
2004 Effect of increasing the expression of cholesterol transporters (StAR, MLN64, and SCP-2) on bile acid synthesis. Journal of lipid research 56 15342684
2004 Molten globule structure and steroidogenic activity of N-218 MLN64 in human placental mitochondria. Endocrinology 51 14715710
2022 Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling. Clinical and translational medicine 47 35678098
2002 MENTHO, a MLN64 homologue devoid of the START domain. The Journal of biological chemistry 45 12393907
2008 Cholesterol interaction with the related steroidogenic acute regulatory lipid-transfer (START) domains of StAR (STARD1) and MLN64 (STARD3). The FEBS journal 43 18331352
2006 MLN64 and MENTHO, two mediators of endosomal cholesterol transport. Biochemical Society transactions 41 16709157
2013 PPP1R1B-STARD3 chimeric fusion transcript in human gastric cancer promotes tumorigenesis through activation of PI3K/AKT signaling. Oncogene 39 24276243
2010 Overexpression of STARD3 in human monocyte/macrophages induces an anti-atherogenic lipid phenotype. Clinical science (London, England : 1979) 36 20491656
2016 Structure of the lutein-binding domain of human StARD3 at 1.74 Å resolution and model of a complex with lutein. Acta crystallographica. Section F, Structural biology communications 31 27487925
2000 Evidence that StAR and MLN64 act on the outer mitochondrial membrane as molten globules. Endocrine research 30 11196440
2012 Cellular adaptation to anthrax lethal toxin-induced mitochondrial cholesterol enrichment, hyperpolarization, and reactive oxygen species generation through downregulating MLN64 in macrophages. Molecular and cellular biology 28 23028046
2003 Metastatic lymph node 64 (MLN64), a gene overexpressed in breast cancers, is regulated by Sp/KLF transcription factors. Oncogene 28 12802284
2016 Relationship between Concentrations of Lutein and StARD3 among Pediatric and Geriatric Human Brain Tissue. PloS one 27 27205891
2012 MLN64 transport to the late endosome is regulated by binding to 14-3-3 via a non-canonical binding site. PloS one 24 22514632
2005 BmStart1, a novel carotenoid-binding protein isoform from Bombyx mori, is orthologous to MLN64, a mammalian cholesterol transporter. Biochemical and biophysical research communications 22 16169523
2021 STARD3: A Prospective Target for Cancer Therapy. Cancers 21 34572920
2019 First-of-its-kind STARD3 Inhibitor: In Silico Identification and Biological Evaluation as Anticancer Agent. ACS medicinal chemistry letters 20 30996782
2016 Touché! STARD3 and STARD3NL tether the ER to endosomes. Biochemical Society transactions 20 27068960
2013 Association analysis of ERBB2 amplicon genetic polymorphisms and STARD3 expression with risk of gastric cancer in the Chinese population. Gene 18 24291029
2023 STARD3: A New Biomarker in HER2-Positive Breast Cancer. Cancers 17 36672312
2007 Overexpression of the cholesterol-binding protein MLN64 induces liver damage in the mouse. World journal of gastroenterology 17 17589922
2014 Mitochondrial proteases act on STARD3 to activate progesterone synthesis in human syncytiotrophoblast. Biochimica et biophysica acta 15 25459514
2010 Expression of MLN64 influences cellular matrix adhesion of breast cancer cells, the role for focal adhesion kinase. International journal of molecular medicine 14 20198306
2018 MLN64 deletion suppresses RANKL-induced osteoclastic differentiation and attenuates diabetic osteoporosis in streptozotocin (STZ)-induced mice. Biochemical and biophysical research communications 12 30322615
2024 Blockade of STARD3-mediated cholesterol transport alleviates diabetes-induced podocyte injury by reducing mitochondrial cholesterol accumulation. Life sciences 11 38754814
2022 Inhibiting the expression of STARD3 induced apoptosis via the inactivation of PI3K/AKT/mTOR pathway on ER+ breast cancer. Tissue & cell 8 36375355
2018 Knocking down Stard3 decreases adipogenesis with decreased mitochondrial ROS in 3T3-L1 cells. Biochemical and biophysical research communications 7 29908180
2024 The lysosomal lipid transporter LIMP-2 is part of lysosome-ER STARD3-VAPB-dependent contact sites. Journal of cell science 6 39370902
2023 Methionine sulfoxide reductases and cholesterol transporter STARD3 constitute an efficient system for detoxification of cholesterol hydroperoxides. The Journal of biological chemistry 5 37507014
2023 StAR-related lipid transfer domain protein 3 (STARD3) regulates HER2 and promotes HER2-positive breast cancer progression through interaction with HSP90 and SRC signaling. American journal of cancer research 5 38058811
2021 Overexpression of STARD3 attenuates oxidized LDL-induced oxidative stress and inflammation in retinal pigment epithelial cells. Biochimica et biophysica acta. Molecular and cell biology of lipids 5 33771709
2023 The ultrastructural function of MLN64 in the late endosome-mitochondria membrane contact sites in placental cells. Experimental cell research 4 37245582
2024 Is STARD3 A New Biomarker for Breast Cancer? European journal of breast health 3 38571685
2026 STARD3 regulates lysosome positioning and contacts via a GSK3-controlled phosphorylation switch. The EMBO journal 0 41741634
2026 STARD3-like protein from golden noble scallop is a carotenoid transfer protein capable of binding various xanthophylls. International journal of biological macromolecules 0 41932487
2026 Erratum: StAR-related lipid transfer domain protein 3 (STARD3) regulates HER2 and promotes HER2-positive breast cancer progression through interaction with HSP90 and SRC signaling. American journal of cancer research 0 42266747
2025 Optimization of Human STARD3 Cholesterol Transporter Expression for Enhancing Bovine P450scc-Mediated Steroid Biotransformation in E. coli. Molecular biotechnology 0 40844562
2024 Metastatic Lymph Node 64 (MLN64) Expression in Gastric Cancer: The Clinical and Molecular Implications in Drug Resistance. Cancer genomics & proteomics 0 38151289
2024 Detection of novel PPP1R1B::STARD3 fusion transcript in acute myeloid leukemia: a case report. Journal of medical case reports 0 38835078

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