Affinage

OSBPL2

Oxysterol-binding protein-related protein 2 · UniProt Q9H1P3

Length
480 aa
Mass
55.2 kDa
Annotated
2026-06-10
22 papers in source corpus 17 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OSBPL2 is a lipid-handling protein that governs cellular cholesterol and phosphoinositide homeostasis and links these lipid functions to AMPK signaling, autophagy, and the structural integrity of cochlear hair cells (PMID:31427568, PMID:35041619, PMID:42191057). It tethers the endoplasmic reticulum to lipid droplets, binds COPB1, and is required for delivery of ATGL to the lipid droplet surface, thereby enabling lipolysis (PMID:32650117). Loss of OSBPL2 reduces AMPK activity and de-represses the SREBP2/HMGCR/HMGCS1 axis and squalene epoxidase (SQLE) by permitting SP1 and SREBF2 occupancy of the SQLE promoter, driving cholesterol and cholesteryl ester accumulation and elevated ROS (PMID:31427568, PMID:31356817); OSBPL2 transcription is itself repressed by 25-hydroxycholesterol through p53/SREBF2/NFYA, embedding it in a sterol-responsive feedback loop (PMID:30391516). Through AMPK-TFEB it sustains autophagic flux and prevents pathological lipid droplet accumulation (PMID:42191057). At the ciliary base, OSBPL2 restrains PI(4,5)P2 levels on cilia membranes to permit ciliogenesis and Sonic Hedgehog signaling, a defect rescued by INPP5E (PMID:35041619). In hair cells it supports the actin cytoskeleton and stereocilia via Rho/ROCK2 and phosphorylated ERM proteins (PMID:40391522). OSBPL2 also stabilizes PLCB3 by inhibiting its ubiquitylation (PMID:38701954) and binds HSP90β to influence ACSL4-dependent ferroptosis and hepatic fatty acid distribution (PMID:42006332). Frameshift mutations cause a toxic gain-of-function proteinopathy: mutant protein accumulates, sequesters autophagy machinery, and impairs endolysosomal homeostasis to produce progressive sensorineural hearing loss (DFNA67), with transgenic mutant—but not knockout—mice recapitulating deafness and rapamycin partially rescuing both protein accumulation and hearing (PMID:35253614).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2015 Medium

    Establishing where OSBPL2 acts in the inner ear was the first step toward understanding its role in hearing, by localizing it to the stereocilia of cochlear hair cells.

    Evidence Immunohistochemistry in mouse cochlea, alongside a reported DIAPH1 interaction

    PMID:25759012

    Open questions at the time
    • DIAPH1 interaction not demonstrated by Co-IP or pulldown in this work
    • no functional consequence of localization tested
  2. 2018 Medium

    Identifying how OSBPL2 expression is controlled placed it within a sterol-responsive feedback circuit, showing that 25-hydroxycholesterol represses its transcription.

    Evidence Dual-luciferase reporters, transcriptomics, and RNAi in HeLa cells implicating p53/SREBF2/NFYA and NFYA promoter binding

    PMID:30391516

    Open questions at the time
    • promoter mechanism mapped in a single cell line
    • physiological relevance to cochlea not addressed
  3. 2019 High

    Defining the downstream signaling consequence of OSBPL2 loss revealed it as an upstream suppressor of cholesterol biosynthesis acting through AMPK and the SREBP2/SQLE transcriptional program.

    Evidence CRISPR KO in OC1/HeLa cells and zebrafish, RNA-seq, luciferase reporters, RNAi, Co-IP with the AMPK activator ATIC, and cholesterol/ROS assays

    PMID:31356817 PMID:31427568

    Open questions at the time
    • direct lipid-transfer activity of OSBPL2 not biochemically reconstituted
    • mechanism by which OSBPL2 promotes AMPK activity beyond ATIC binding unresolved
  4. 2019 High

    A large-animal model connected OSBPL2 disruption causally to both progressive hair-cell degeneration and systemic hypercholesterolaemia, with diet modifying severity.

    Evidence CRISPR-edited Bama miniature pigs with auditory testing, histology, and serum lipid profiling

    PMID:31451425

    Open questions at the time
    • does not distinguish cell-autonomous cochlear effects from systemic lipid effects
    • molecular trigger of hair-cell apoptosis not pinpointed
  5. 2019 Medium

    Linking OSBPL2 to focal adhesion and FAK activity began to explain its role in hair-cell structural integrity beyond lipid metabolism.

    Evidence CRISPR KO in OC1 cells with focal adhesion staining and FAK activity assays

    PMID:31629475

    Open questions at the time
    • mechanistic connection between lipid handling and FAK signaling unestablished
    • single cell-line model
  6. 2020 Medium

    Resolving OSBPL2's molecular function at organelle contacts showed it scaffolds the ER-lipid droplet interface to deliver the lipolytic enzyme ATGL.

    Evidence Co-IP with COPB1, localization studies, and lipolysis assays in KO cells

    PMID:32650117

    Open questions at the time
    • direct lipid cargo of OSBPL2 in this process not identified
    • single lab without reciprocal structural validation
  7. 2022 High

    Distinguishing loss-of-function from gain-of-function resolved the disease mechanism: mutant OSBPL2 protein, not its absence, causes deafness via a toxic autophagy-impairing proteinopathy.

    Evidence Transgenic mutant vs KO mice, Co-IP with autophagy proteins, endolysosomal assays, and rapamycin rescue in mice and patients

    PMID:35253614

    Open questions at the time
    • specific autophagy proteins sequestered not all defined
    • durability of rapamycin benefit in patients not established
  8. 2022 High

    Identifying a ciliary phosphoinositide function explained how OSBPL2 supports ciliogenesis and Hedgehog signaling, by restraining PI(4,5)P2 at the cilium.

    Evidence Osbpl2-KO mice, ciliary localization, PI(4,5)P2 quantification, INPP5E overexpression rescue, and Shh pathway Western blots

    PMID:35041619

    Open questions at the time
    • whether OSBPL2 directly transports PI(4,5)P2 or recruits phosphatases unresolved
    • link between ciliary defect and hearing loss not directly tested
  9. 2024 Medium

    A new substrate-stabilization role emerged, showing OSBPL2 protects PLCB3 from ubiquitin-mediated degradation, with relevance to epidermal differentiation.

    Evidence Exome sequencing, Co-IP, ubiquitylation assays, and keratinocyte proliferation/differentiation assays

    PMID:38701954

    Open questions at the time
    • E3 ligase acting on PLCB3 not identified
    • mechanism by which OSBPL2 blocks ubiquitylation undefined
  10. 2024 Medium

    OSBPL2 was characterized as a tumor suppressor in colorectal cancer whose loss activates ERK and pro-metastatic programs.

    Evidence KO/knockdown CRC lines, migration/invasion assays, and ERK and PARP1 inhibitor epistasis

    PMID:38267463

    Open questions at the time
    • how lipid function connects to VCAN/AREG/EREG-ERK axis unclear
    • single-lab in vitro emphasis
  11. 2024 Medium

    An additional survival pathway was mapped, linking OSBPL2 to protection against oxidative apoptosis through AKT-FOXG1 in auditory cells.

    Evidence siRNA knockdown in H2O2-treated HEI-OC1 cells with AKT/FOXG1 pharmacological and genetic epistasis

    PMID:39475791

    Open questions at the time
    • how OSBPL2 modulates AKT activity not defined
    • in vivo relevance not tested
  12. 2025 Medium

    Cytoskeletal regulation was tied to Rho/ROCK2-pERM signaling, explaining stereociliary defects upon OSBPL2 loss.

    Evidence Osbpl2-KO mice and knockdown HEI-OC1 cells with Rho/ROCK2 activity assays and p-ERM/F-actin imaging

    PMID:40391522

    Open questions at the time
    • upstream link from OSBPL2 lipid function to Rho activation unknown
    • single lab
  13. 2025 Medium

    A vascular contribution to deafness was identified, with OSBPL2 maintaining the cochlear blood-labyrinth barrier and suppressing NF-κB-driven inflammatory apoptosis.

    Evidence Osbpl2-KO mice, FITC-dextran permeability, OSBPL2-deficient HUVECs, tight-junction imaging, and NF-κB analysis

    PMID:40975921

    Open questions at the time
    • mechanism linking OSBPL2 to tight-junction maintenance undefined
    • relative contribution of barrier defect to hearing loss not quantified
  14. 2026 Medium

    Integrating lipid metabolism with cell-death control, OSBPL2 was shown to bind HSP90β and modulate ACSL4-dependent ferroptosis and hepatic fatty acid distribution.

    Evidence Co-IP with HSP90β, OSBPL2 KO mice, ferroptosis assays, and lipolysis measurements

    PMID:42006332

    Open questions at the time
    • how HSP90β binding controls ACSL4 expression unresolved
    • single-lab finding
  15. 2026 Medium

    The AMPK-cholesterol axis was extended to autophagy and cancer, showing OSBPL2 sustains AMPK-TFEB autophagy and suppresses lipid-droplet-driven stemness and tumorigenesis.

    Evidence Osbpl2-KO mice and HEI-OC1 cells with autophagy flux assays and trehalose rescue; cholesterol quantification, sphere assays, and xenograft models in lung cancer

    PMID:41645290 PMID:42191057

    Open questions at the time
    • whether autophagy and tumor-suppressive effects share one upstream lipid-transfer event unclear
    • tissue specificity of OSBPL2's metabolic outputs not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct lipid-transfer activity and bona fide lipid cargo of OSBPL2 remain to be defined biochemically, which would unify its disparate cholesterol, phosphoinositide, and lipid-droplet roles into a single molecular mechanism.
  • no reconstituted lipid-transfer assay in the corpus
  • no structural model of OSBPL2 with lipid cargo
  • mechanistic unification across tissues unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 1
Localization
GO:0005811 lipid droplet 2 GO:0005856 cytoskeleton 2 GO:0005783 endoplasmic reticulum 1 GO:0005929 cilium 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2
Partners
ATICCOPB1DIAPH1HSP90B1PLCB3

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 OSBPL2 protein is expressed in stereocilia of cochlear outer and inner hair cells in mice, as determined by immunohistochemistry, placing it in a structural compartment critical for hearing. Immunohistochemistry in mouse cochlea Orphanet journal of rare diseases Medium 25759012
2015 OSBPL2 protein interacts with DIAPH1 (the DFNA1 protein), placing OSBPL2 in a complex with a known deafness-associated formin. Protein-protein interaction reported in context of frameshift mutation identification Orphanet journal of rare diseases Low 25759012
2019 OSBPL2 deficiency reduces AMPK activity and upregulates SREBP2, HMGCR, and HMGCS1, leading to increased cholesterol biosynthesis and elevated ROS in auditory OC1 cells and zebrafish inner ear; OSBPL2 interacts with ATIC, a known AMPK activator. CRISPR/Cas9 KO in OC1 cells and zebrafish, RNA-seq, cholesterol/ROS assays, Co-IP (OSBPL2–ATIC interaction), mitochondrial morphology assessment Cell death & disease High 31427568
2019 OSBPL2 deficiency upregulates squalene epoxidase (SQLE) expression via AMPK signaling inhibition, which allows SP1 and SREBF2 to enter the nucleus and bind functional sites in the SQLE promoter, increasing intracellular cholesterol and cholesteryl ester accumulation. CRISPR/Cas9 KO in HeLa cells, RNA-seq, dual-luciferase reporter assay, RNA interference of AMPK pathway components Experimental cell research High 31356817
2019 OSBPL2-disrupted pigs exhibit progressive hearing loss with degeneration/apoptosis of cochlear hair cells and morphological abnormalities of hair cell stereocilia, as well as hypercholesterolaemia; high-fat diet aggravates both phenotypes. CRISPR/Cas9-mediated gene editing in Bama miniature pigs, somatic cell nuclear transfer, auditory function testing, histology, serum lipid profiling Journal of genetics and genomics High 31451425
2019 OSBPL2 deficiency impairs focal adhesion morphology and inhibits FAK activity, resulting in impaired cell adhesion in auditory OC1 cells. CRISPR/Cas9 KO in OC1 cells, RNA-seq, focal adhesion staining, FAK activity assay Biochemical and biophysical research communications Medium 31629475
2018 25-hydroxycholesterol (25-OHC) decreases OSBPL2 transcription via the p53/SREBF2/NFYA signaling pathway; NFYA and PLAG1 participate in basal transcription of OSBPL2, and 25-OHC reduces NFYA binding to the OSBPL2 promoter. Dual-luciferase reporter assay, transcriptome sequencing, RNA interference in HeLa cells The Journal of steroid biochemistry and molecular biology Medium 30391516
2020 OSBPL2 links the endoplasmic reticulum with lipid droplets, binds to COPB1, and is required for ATGL transport from the ER to the lipid droplet surface, thereby regulating lipid droplet lipolysis. Co-IP, cellular localization studies, KO cell lines, lipolysis assays iScience Medium 32650117
2022 Mutant OSBPL2 (frameshift) accumulates intracellularly, binds autophagy proteins, causes defective endolysosomal homeostasis and impaired autophagy; transgenic mice expressing mutant OSBPL2 develop hearing loss, while OSBPL2 KO mice do not, establishing a toxic gain-of-function proteinopathy mechanism; rapamycin reduces mutant protein accumulation and partially rescues hearing loss. Transgenic and KO mouse models, Co-IP with autophagy proteins, endolysosomal assays, rapamycin treatment in mice and human patients (clinical trial component) Autophagy High 35253614
2022 OSBPL2 localizes to the base of kinocilia in hair cells and primary cilia in supporting cells; OSBPL2 deficiency increases PI(4,5)P2 on cilia membranes, disrupts ciliogenesis, and downregulates smoothened and GLI3 in the Sonic Hedgehog (Shh) signaling pathway; overexpression of INPP5E partially rescues the PI(4,5)P2 accumulation. Osbpl2-KO mice, immunofluorescence localization, PI(4,5)P2 membrane assay, INPP5E overexpression rescue, Western blot for Shh pathway components JCI insight High 35041619
2024 OSBPL2 directly interacts with PLCB3 and inhibits its ubiquitylation, thereby stabilizing PLCB3; OSBPL2 variants lead to enhanced ubiquitination and degradation of PLCB3, causing epidermal hyperkeratosis with aberrant keratinocyte proliferation and delayed terminal differentiation. Exome sequencing, Co-IP (OSBPL2–PLCB3 interaction), ubiquitylation assay, cell proliferation/differentiation assays Biochimica et biophysica acta. Molecular basis of disease Medium 38701954
2024 OSBPL2 loss activates ERK signaling through the VCAN/AREG/EREG axis and promotes metastasis via PARP1/ZEB1 in colorectal cancer cells; OSBPL2 deficiency supports focal adhesion, migration, and invasion induced by Collagen I. KO/knockdown CRC cell lines, migration/invasion assays, ERK pathway inhibitor (SCH772984), PARP1 inhibitor (AG14361), Western blot Cell death & disease Medium 38267463
2025 OSBPL2 deficiency inhibits the Rho/ROCK2 signaling pathway and downregulates phosphorylated ERM proteins (p-ERM), resulting in abnormal F-actin morphology in HEI-OC1 auditory cells and stereociliary defects in mouse hair cells. OSBPL2-knockdown HEI-OC1 cells and Osbpl2-KO mice, Rho/ROCK2 activity assays, immunofluorescence of p-ERM and F-actin Journal of biomedical research Medium 40391522
2025 OSBPL2 is highly expressed in the stria vascularis; OSBPL2 deficiency increases cochlear blood-labyrinth barrier permeability, disrupts tight junctions in stria vascularis endothelium, and induces inflammation-mediated apoptosis via NF-κB signaling activation. Osbpl2-KO mice, FITC-dextran permeability assay, OSBPL2-deficient HUVECs, immunofluorescent staining of tight junction proteins, NF-κB pathway analysis Hearing research Medium 40975921
2024 OSBPL2 knockdown in H2O2-treated HEI-OC1 cells augments apoptosis by inhibiting the AKT signaling pathway and subsequently inactivating FOXG1; AKT activation partially rescues apoptosis in OSBPL2-knockdown cells, and this rescue is reversed by FOXG1 silencing. siRNA knockdown in HEI-OC1 cells, AKT inhibitor (MK2206) and activator (SC79), FOXG1 siRNA, apoptosis assays, Western blot Aging Medium 39475791
2026 OSBPL2 deficiency impairs autophagy by inhibiting the AMPK-TFEB signaling pathway, causing aberrant lipid droplet accumulation and apoptosis in auditory hair cells; trehalose treatment partially reverses these effects. Osbpl2-KO mice, Osbpl2-knockdown HEI-OC1 cells, autophagy flux assays, AMPK-TFEB pathway analysis, trehalose rescue Cellular signalling Medium 42191057
2026 OSBPL2 binds to HSP90β; OSBPL2 deficiency inhibits ACSL4 expression and alters hepatic fatty acid distribution by impairing lipolysis, conferring resistance to ferroptosis via the ACSL4-mediated ferroptosis pathway. Co-IP (OSBPL2–HSP90β), OSBPL2 KO mouse model, ferroptosis assays, lipolysis measurements iScience Medium 42006332
2026 OSBPL2 reduces cholesterol content and inhibits lipid droplet accumulation in lung cancer cells; OSBPL2-mediated lipid transport suppresses tumor sphere formation, stemness marker expression, and in vivo tumorigenesis and metastasis. HPLC-MS cholesterol quantification, lipid droplet staining, tumor sphere assay, xenograft/metastasis mouse models, OSBPL2 overexpression Stem cell research & therapy Medium 41645290

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 50 25077649
2015 OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67). Orphanet journal of rare diseases 44 25759012
2019 Deletion of OSBPL2 in auditory cells increases cholesterol biosynthesis and drives reactive oxygen species production by inhibiting AMPK activity. Cell death & disease 33 31427568
2022 OSBPL2 mutations impair autophagy and lead to hearing loss, potentially remedied by rapamycin. Autophagy 31 35253614
2019 OSBPL2 deficiency upregulate SQLE expression increasing intracellular cholesterol and cholesteryl ester by AMPK/SP1 and SREBF2 signalling pathway. Experimental cell research 30 31356817
2020 OSBPL2 Is Required for the Binding of COPB1 to ATGL and the Regulation of Lipid Droplet Lipolysis. iScience 29 32650117
2019 OSBPL2-disrupted pigs recapitulate dual features of human hearing loss and hypercholesterolaemia. Journal of genetics and genomics = Yi chuan xue bao 24 31451425
2021 Circ-OSBPL2 Contributes to Smoke-Related Chronic Obstructive Pulmonary Disease by Targeting miR-193a-5p/BRD4 Axis. International journal of chronic obstructive pulmonary disease 20 33854310
2024 Collagen I-induced VCAN/ERK signaling and PARP1/ZEB1-mediated metastasis facilitate OSBPL2 defect to promote colorectal cancer progression. Cell death & disease 19 38267463
2022 circRNA Acbd6 promotes neural stem cell differentiation into cholinergic neurons via the miR-320-5p-Osbpl2 axis. The Journal of biological chemistry 17 35305988
2022 Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via sonic hedgehog signaling. JCI insight 16 35041619
2019 A novel pathogenic variant in OSBPL2 linked to hereditary late-onset deafness in a Mongolian family. BMC medical genetics 11 30894143
2019 Comparative transcriptome analysis of auditory OC-1 cells and zebrafish inner ear tissues in the absence of human OSBPL2 orthologues. Biochemical and biophysical research communications 6 31629475
2018 25-hydroxycholesterol down-regulates oxysterol binding protein like 2 (OSBPL2) via the p53/SREBF2/NFYA signaling pathway. The Journal of steroid biochemistry and molecular biology 6 30391516
2025 OSBPL2 deficiency impaired cochlear blood-labyrinth barrier via activation of NF-κB signaling pathway. Hearing research 2 40975921
2024 OSBPL2 inhibition leads to apoptosis of cochlea hair cells in age-related hearing loss by inhibiting the AKT/FOXG1 signaling pathway. Aging 2 39475791
2025 OSBPL2 deficiency inhibits Rho/ROCK2/p-ERM signaling and impairs actin cytoskeletal regulation in auditory cells. Journal of biomedical research 1 40391522
2026 OSBPL2-mediated lipid metabolism alteration governs lung cancer stem cells properties. Stem cell research & therapy 0 41645290
2026 OSBPL2 deficiency alleviates diet-induced MASLD by reducing ACSL4-mediated ferroptosis. iScience 0 42006332
2026 OSBPL2 deficiency impaired autophagy and induced apoptosis in auditory cells via AMPK-TFEB signalling pathway. Cellular signalling 0 42191057
2025 [OSBPL2-related autosomal dominant hearing loss: a family analysis and literature review]. Zhonghua yi xue za zhi 0 41017354
2024 OSBPL2 compound heterozygous variants cause dyschromatosis, ichthyosis, deafness and atopic disease syndrome. Biochimica et biophysica acta. Molecular basis of disease 0 38701954

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