STARD10

STARD10 is a START-domain phospholipid transfer protein that selectively binds and shuttles phosphatidylcholine and phosphatidylethanolamine between membranes, with a preference for species bearing a saturated sn-1 and unsaturated sn-2 acyl chain, distinguishing it from related START proteins (PMID:15911624). Crystallographic and lipid-binding analysis showed its pocket also accommodates polyphosphoinositides phosphorylated at the 3' position, linking its activity to cellular phosphoinositide composition (PMID:32416313). Its transfer activity is negatively regulated by casein kinase II phosphorylation at Ser284, which reduces lipid transfer and modulates membrane association (PMID:17561512). In pancreatic β-cells, STARD10 controls glucose-stimulated insulin secretion, Ca2+ dynamics, dense-core granule morphology, and proinsulin processing, establishing it as the causal gene at a type 2 diabetes GWAS locus over the neighboring ARAP1 (PMID:28132686, PMID:33535042); it binds the inositol lipid kinase PIP4K2C, tying its function to phosphoinositide metabolism in the secretory pathway (PMID:32416313). Beyond β-cells, STARD10 directly interacts with LPCAT1 via its START domain to traffic surfactant phospholipids from the ER to lamellar bodies in alveolar type II cells (PMID:26048993), regulates hepatic bile acid homeostasis through PPARα signaling (PMID:23200860), and in steatotic liver drives ferroptosis upstream of a YBX1–ACSL1 axis (PMID:41943848). STARD10 is overexpressed in ErbB2-positive breast tumors and cooperates with ErbB receptor signaling to promote anchorage-independent growth (PMID:15150109, PMID:30611309).

1. 2004 Medium

   Established the first functional link for STARD10 to disease, showing it is a phosphoprotein overexpressed in ErbB2-positive tumors that cooperates with ErbB signaling in transformation.

   Evidence Soft agar anchorage-independent growth assay with StarD10/EGFR co-expression in murine fibroblasts and biochemical purification

   PMID:15150109

   Open questions at the time

   • Molecular mechanism connecting lipid transfer to transformation not defined
   • Phosphorylation site not mapped in this work
2. 2005 High

   Defined the core biochemical activity, demonstrating STARD10 is a selective PC/PE transfer protein distinct from other START proteins.

   Evidence ESR, FRET lipid binding, radiolabeled vesicle extraction, mass spectrometry, and in-cell photoactivatable lipid cross-linking

   PMID:15911624

   Open questions at the time

   • Physiological membranes/organelles served not identified
   • Phosphoinositide binding not yet recognized
3. 2005 Medium

   Identified STARD10 as a phosphoprotein and mapped an initial phosphorylation site, raising the question of regulated activity.

   Evidence Immunoaffinity purification, IMAC phosphopeptide enrichment, and tandem MS of Flag-tagged protein from HEK-293T

   PMID:15704244

   Open questions at the time

   • No functional consequence of the identified site tested
   • Responsible kinase not identified
4. 2007 High

   Showed lipid transfer is regulated post-translationally, identifying CKII phosphorylation at Ser284 as a negative switch on STARD10 activity.

   Evidence In vitro CKII kinase assay with S284A mutant plus lipid transfer assays using cell extracts and purified recombinant protein

   PMID:17561512

   Open questions at the time

   • Upstream signals controlling CKII action on STARD10 unknown
   • Membrane association mechanism not structurally defined
5. 2012 Medium

   Revealed a physiological role in the liver, linking STARD10 loss to disrupted bile acid homeostasis via impaired PPARα signaling.

   Evidence Stard10 knockout mice with bile acid measurement, ASBT and PPARα target gene analysis, and hepatoma cell assays

   PMID:23200860

   Open questions at the time

   • Direct biochemical link between lipid transfer and PPARα activity not established
   • Single lab, single model
6. 2015 High

   Connected STARD10 lipid transfer to a defined trafficking pathway by showing direct START-domain interaction with LPCAT1 enables surfactant phospholipid delivery to lamellar bodies.

   Evidence Co-IP, domain-mapped direct binding assays, and siRNA knockdown with lamellar body phospholipid trafficking assay in alveolar type II cells

   PMID:26048993

   Open questions at the time

   • Whether transfer activity vs scaffolding drives trafficking unresolved
   • Regulation of the interaction not defined
7. 2017 High

   Resolved which gene at a T2D GWAS locus is causal, establishing STARD10 (not ARAP1) as a controller of β-cell insulin secretion and proinsulin processing.

   Evidence β-cell-selective Stard10 KO and overexpression mice with GSIS, Ca2+ imaging, proinsulin:insulin ratio, and Arap1 negative control

   PMID:28132686

   Open questions at the time

   • Molecular mechanism linking lipid handling to granule biogenesis not yet defined
   • Human cell confirmation pending at this stage
8. 2020 High

   Provided the structural and lipidomic basis for β-cell function, showing STARD10 binds 3'-phosphoinositides and partners with PIP4K2C to shape granule biology.

   Evidence 2.3 Å crystal structure, molecular docking, lipid overlay, KO islet lipidomics and electron microscopy, secretion assays, and Co-IP/MS proteomics

   PMID:32416313

   Open questions at the time

   • Functional consequence of PIP4K2C binding not mechanistically dissected
   • How phosphoinositide handling alters granule morphology unresolved
9. 2021 Medium

   Confirmed the β-cell secretory role in a human system, removing ambiguity about species- or model-specific effects.

   Evidence CRISPR-Cas9 deletion in human EndoC-βH1 cells with glucose-stimulated insulin secretion assay

   PMID:33535042

   Open questions at the time

   • Single human cell line
   • Upstream lipid mechanism not re-tested here
10. 2019 Medium

    Detailed how ErbB2 signaling and STARD10 reinforce each other transcriptionally, with STARD10 feeding back through membrane fluidity and calcium to ErbB2 signaling.

    Evidence Promoter activity assays, knockdown/overexpression in breast cancer cells, calcium and membrane fluidity assays, and p65 promoter-binding assessment

    PMID:30611309

    Open questions at the time

    • Direct biochemical role of lipid transfer in the feedback loop unproven
    • In vivo tumor relevance not established
11. 2026 Medium

    Identified a pro-ferroptotic function in steatotic liver, placing STARD10 upstream of a YBX1–ACSL1 transcriptional axis controlling lipid peroxidation.

    Evidence Hepatocyte-specific AAV8 KO/OE, CRISPR, Co-IP/MS, lipidomics, transcriptomics, YBX1 promoter binding, and ACSL1 rescue experiment

    PMID:41943848

    Open questions at the time

    • How STARD10 controls YBX1 nuclear translocation mechanistically unclear
    • Single lab, single injury model
12. 2026 Medium

    Extended β-cell relevance to human development and metabolism, showing STARD10 supports β-like cell formation and lipid oxidation capacity.

    Evidence STARD10 deletion in human ESC-derived β-like cells with lipidomics, RNA-seq, Seahorse metabolic assays, and flow cytometry

    PMID:41687621

    Open questions at the time

    • Causal link between lipid transfer and differentiation defect not established
    • Mechanism of metabolic impairment not pinpointed

• How STARD10's single biochemical activity—regulated phospholipid/phosphoinositide transfer—mechanistically produces its tissue-specific roles across β-cell secretion, surfactant trafficking, bile acid metabolism, ferroptosis, and ErbB-driven transformation remains unresolved.
• No unified model linking lipid transfer to downstream transcriptional axes (PPARα, YBX1-ACSL1)
• Membrane contact sites and donor/acceptor compartments in vivo undefined
• Regulation of partner selection (LPCAT1 vs PIP4K2C) across tissues unknown