Affinage

OSBPL2

Oxysterol-binding protein-related protein 2 · UniProt Q9H1P3

Length
480 aa
Mass
55.2 kDa
Annotated
2026-04-29
21 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

OSBPL2 is a lipid transfer protein that integrates cholesterol homeostasis, phosphoinositide regulation, and cytoskeletal organization across multiple cell types. It maintains intracellular cholesterol levels by sustaining AMPK activity through interaction with ATIC, thereby suppressing SREBP2-driven cholesterol biosynthesis genes including SQLE and HMGCR (PMID:31427568, PMID:31356817); it also bridges the endoplasmic reticulum to lipid droplets via COPB1 binding to mediate ATGL transport and lipid droplet lipolysis (PMID:32650117). In cochlear hair cells, OSBPL2 controls cilia membrane PI(4,5)P2 levels and Sonic Hedgehog signaling to support ciliogenesis, and maintains stereocilia architecture through Rho/ROCK2/phospho-ERM–dependent actin organization (PMID:35041619, PMID:40391522). Frameshift mutations in OSBPL2 cause autosomal dominant hearing loss (DFNA67) through a toxic gain-of-function proteinopathy in which mutant protein accumulates, sequesters autophagy machinery, and disrupts endolysosomal homeostasis—a phenotype partially rescued by rapamycin (PMID:35253614).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2015 Medium

    Establishing OSBPL2 as a cochlear protein: its localization to stereocilia of hair cells and interaction with the deafness protein DIAPH1 placed it in the auditory mechanotransduction apparatus for the first time.

    Evidence Immunohistochemistry in mouse cochlea with protein interaction context

    PMID:25759012

    Open questions at the time
    • DIAPH1 interaction not validated by reciprocal Co-IP
    • Functional consequence of stereociliary localization untested
    • No hearing phenotype demonstrated
  2. 2018 Medium

    Understanding OSBPL2 transcriptional regulation: 25-hydroxycholesterol was shown to repress OSBPL2 transcription via p53/SREBF2/NFYA, revealing a feedback loop linking oxysterol sensing to OSBPL2 expression.

    Evidence Dual-luciferase reporter assay and RNAi in HeLa cells

    PMID:30391516

    Open questions at the time
    • In vivo relevance of oxysterol-mediated feedback not tested
    • Whether other oxysterols similarly regulate OSBPL2 is unknown
  3. 2019 Medium

    Defining the cholesterol-regulatory mechanism: OSBPL2 loss was shown to decrease AMPK activity (via lost ATIC interaction), de-repress SREBP2 and its targets HMGCR/HMGCS1/SQLE, and elevate intracellular cholesterol and ROS, establishing OSBPL2 as a cholesterol homeostasis regulator acting through AMPK signaling.

    Evidence CRISPR KO in OC1 cells and zebrafish, Co-IP for OSBPL2–ATIC, RNA-seq, dual-luciferase reporter for SQLE promoter

    PMID:31356817 PMID:31427568

    Open questions at the time
    • ATIC interaction validated by single Co-IP without domain mapping
    • Whether OSBPL2 lipid-binding activity is required for AMPK regulation is unknown
    • Cell adhesion and FAK impairment noted but mechanistic link to cholesterol not resolved
  4. 2020 Medium

    Revealing a lipid droplet tethering function: OSBPL2 was found to physically bridge the ER to lipid droplets through COPB1 interaction and to transport ATGL to lipid droplet surfaces, providing a direct mechanism for its role in lipolysis.

    Evidence Co-IP for OSBPL2–COPB1, subcellular fractionation, KO cell lipolysis assays

    PMID:32650117

    Open questions at the time
    • Structural basis of ER–lipid droplet tethering undefined
    • Whether lipid transfer activity is required for ATGL transport not tested
    • COPB1 interaction not confirmed by independent lab
  5. 2022 High

    Establishing the disease mechanism for DFNA67: transgenic mice expressing frameshift mutant OSBPL2 developed hearing loss while KO mice did not, proving a toxic gain-of-function proteinopathy in which mutant protein sequesters autophagy machinery and impairs endolysosomal function; rapamycin partially rescued the phenotype.

    Evidence Transgenic and KO mouse models, Co-IP with autophagy proteins, endolysosomal assays, rapamycin treatment in mice and patients

    PMID:35253614

    Open questions at the time
    • Identity of sequestered autophagy proteins not fully characterized
    • Long-term efficacy of rapamycin in patients unknown
    • Whether all OSBPL2 frameshift mutations produce the same toxic protein unclear
  6. 2022 High

    Uncovering a ciliogenesis role: OSBPL2 localizes to cilia bases and its loss elevates ciliary PI(4,5)P2, impairing ciliogenesis and Sonic Hedgehog signaling (SMO, GLI3); INPP5E overexpression partially rescued the PI(4,5)P2 defect, linking OSBPL2's phosphoinositide regulation to cilium formation.

    Evidence KO mouse and HEI-OC1 cells, immunofluorescence, PI(4,5)P2 quantification, INPP5E rescue

    PMID:35041619

    Open questions at the time
    • Whether OSBPL2 directly transfers PI(4,5)P2 or acts indirectly is unresolved
    • Contribution of ciliogenesis defects versus stereocilia defects to hearing loss not separated
  7. 2024 Medium

    Expanding functional scope: OSBPL2 was shown to stabilize PLCB3 by inhibiting its ubiquitylation, with OSBPL2 variants causing keratinocyte hyperkeratosis, and separately OSBPL2 loss was found to promote colorectal cancer migration via ERK/PARP1/ZEB1 and to sensitize hair cells to apoptosis via AKT/FOXG1 inactivation.

    Evidence Co-IP and ubiquitylation assays for PLCB3; KO colorectal cancer cells with ERK/PARP1 inhibitor rescue; siRNA knockdown with AKT activator/inhibitor rescue in HEI-OC1

    PMID:38267463 PMID:38701954 PMID:39475791

    Open questions at the time
    • PLCB3 stabilization mechanism (which E3 ligase is antagonized) unknown
    • Relevance of colorectal cancer findings to physiological OSBPL2 function unclear
    • AKT/FOXG1 pathway link specific to oxidative stress context
  8. 2025 Medium

    Defining the actin-regulatory and barrier-integrity functions: OSBPL2 deficiency was shown to impair stereocilia through Rho/ROCK2/p-ERM downregulation and to disrupt the cochlear blood-labyrinth barrier via NF-κB–driven tight junction loss and inflammation-mediated apoptosis.

    Evidence KO mouse and HEI-OC1 cells with ROCK2/p-ERM Western blot, SEM of stereocilia; KO mice with FITC-dextran permeability, HUVEC permeability assay, NF-κB analysis

    PMID:40391522 PMID:40975921

    Open questions at the time
    • How OSBPL2 activates RhoA upstream of ROCK2 is undefined
    • Whether NF-κB activation is a direct or secondary consequence of OSBPL2 loss unclear
    • Single-lab findings for both phenotypes
  9. 2025 Medium

    Linking OSBPL2 to ferroptosis: OSBPL2 binds HSP90β and its deficiency suppresses ACSL4, altering hepatic fatty acid composition and conferring ferroptosis resistance that attenuates diet-induced liver fibrosis.

    Evidence Co-IP for OSBPL2–HSP90β, KO mouse on high-fat diet, ferroptosis assays, liver fibrosis phenotyping

    PMID:42006332

    Open questions at the time
    • HSP90β interaction not confirmed by independent lab
    • Mechanism connecting HSP90β binding to ACSL4 expression unresolved
    • Physiological relevance of ferroptosis resistance in normal hepatocytes unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open question: whether OSBPL2's lipid transfer activity is directly required for its diverse signaling roles (AMPK, ciliogenesis, actin regulation), and how a single protein coordinates cholesterol, phosphoinositide, and fatty acid pathways across different tissues remains mechanistically unresolved.
  • No crystal structure or lipid-binding mutant analysis separating transfer activity from scaffolding
  • Tissue-specific interactomes not systematically mapped
  • Relative contribution of loss-of-function versus toxic gain-of-function to DFNA67 pathology in human patients not fully delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005783 endoplasmic reticulum 1 GO:0005811 lipid droplet 1 GO:0005929 cilium 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 1
Partners
ATICCOPB1DIAPH1HSP90AB1PLCB3

Evidence

Reading pass · 14 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, and interacts with the DFNA1 protein DIAPH1 Immunohistochemistry in mouse cochlea; protein interaction noted from literature context Orphanet journal of rare diseases Medium 25759012
2019 OSBPL2 deletion increases cholesterol biosynthesis by reducing AMPK activity, leading to upregulation of SREBP2, HMGCR, and HMGCS1; OSBPL2 interacts with ATIC (a key AMPK activator), and loss of OSBPL2 increases total cholesterol and ROS with mitochondrial damage CRISPR/Cas9 KO in OC1 cells and zebrafish, RNA-seq, Co-IP (OSBPL2–ATIC interaction), biochemical assays for cholesterol and ROS Cell death & disease Medium 31427568
2019 OSBPL2 deficiency upregulates SQLE expression by suppressing AMPK signaling, which allows SP1 and SREBF2 to enter the nucleus and bind functional sites in the SQLE promoter, increasing intracellular cholesterol and cholesteryl ester CRISPR/Cas9 KO HeLa cells, RNA-seq, dual-luciferase reporter assay, RNA interference Experimental cell research Medium 31356817
2019 OSBPL2 deficiency impairs focal adhesion morphology characterized by inhibited FAK activity and impaired cell adhesion in auditory OC-1 cells, with pathway analysis implicating lipid metabolism, cell adhesion, extracellular matrix, and ubiquitination CRISPR/Cas9 KO in OC-1 cells and zebrafish, RNA-seq, protein-protein interaction analysis, cell adhesion assay Biochemical and biophysical research communications Medium 31629475
2018 25-hydroxycholesterol downregulates OSBPL2 transcription via the p53/SREBF2/NFYA signaling pathway; NFYA and PLAG1 participate in basal transcription of OSBPL2 by binding its 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 COPB1, and mediates ATGL transport from the ER to the lipid droplet surface, thereby regulating lipid droplet lipolysis Co-IP (OSBPL2–COPB1 interaction), subcellular fractionation/localization, KO cell lines, functional 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 exhibit hearing loss while KO mice do not, demonstrating toxic gain-of-function proteinopathy; rapamycin decreases mutant accumulation and partially rescues hearing loss Transgenic and KO mouse models, Co-IP (mutant OSBPL2–autophagy protein interaction), endolysosomal assays, rapamycin treatment in mice and human patients Autophagy High 35253614
2022 OSBPL2 localizes to the base of kinocilia in hair cells and primary cilia in supporting cells; its deficiency increases PI(4,5)P2 on the cilia membrane, impairing ciliogenesis; this can be partially rescued by INPP5E overexpression; OSBPL2 deficiency also downregulates SMO and GLI3 in the Sonic Hedgehog signaling pathway KO mouse model, immunofluorescence localization, PI(4,5)P2 quantification, INPP5E rescue experiment, SHH pathway protein analysis in KO HEI-OC1 cells 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 Co-IP (OSBPL2–PLCB3 interaction), ubiquitylation assay, exome sequencing, cell proliferation and differentiation assays Biochimica et biophysica acta. Molecular basis of disease Medium 38701954
2024 OSBPL2 deficiency activates ERK signaling through the VCAN/AREG/EREG axis and promotes cancer cell migration/invasion; OSBPL2 loss also facilitates metastasis via PARP1/ZEB1 pathway in colorectal cancer cells KO/knockdown in colorectal cancer cells, ERK pathway inhibitor (SCH772984) and PARP1 inhibitor (AG14361) rescue, migration/invasion assays Cell death & disease Medium 38267463
2025 OSBPL2 deficiency inhibits Rho/ROCK2 signaling and downregulates phosphorylated ERM (p-ERM), resulting in abnormal F-actin morphology in HEI-OC1 cells and stereociliary defects in mouse hair cells KO mouse model and HEI-OC1 KO cells, Western blot for ROCK2/p-ERM, F-actin staining, scanning electron microscopy of stereocilia Journal of biomedical research Medium 40391522
2025 OSBPL2 deficiency in stria vascularis impairs the cochlear blood-labyrinth barrier by disrupting tight junctions and inducing inflammation-mediated apoptosis via NF-κB signaling activation Osbpl2-KO mice with FITC-dextran permeability assay, OSBPL2-deficient HUVECs endothelial permeability assay, immunofluorescence of tight junctions, NF-κB pathway analysis Hearing research Medium 40975921
2024 OSBPL2 knockdown in H2O2-treated HEI-OC1 cells sensitizes cells to apoptosis by inhibiting the AKT signaling pathway, which in turn inactivates FOXG1; AKT activation by SC79 partially rescues apoptosis in OSBPL2-knockdown cells, and this rescue is reversed by FOXG1 silencing siRNA knockdown, AKT inhibitor (MK2206) and activator (SC79), FOXG1 siRNA rescue experiment, apoptosis assays in HEI-OC1 cells Aging Medium 39475791
2026 OSBPL2 binds HSP90β; OSBPL2 deficiency inhibits ACSL4 expression, alters hepatic fatty acid distribution by impairing lipolysis, and confers resistance to ferroptosis via the ACSL4-mediated ferroptosis pathway, attenuating diet-induced liver fibrosis Co-IP (OSBPL2–HSP90β), KO mouse model on high-fat diet, ACSL4 expression analysis, ferroptosis assays, liver fibrosis phenotyping iScience Medium 42006332

Source papers

Stage 0 corpus · 21 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 30 35253614
2020 OSBPL2 Is Required for the Binding of COPB1 to ATGL and the Regulation of Lipid Droplet Lipolysis. iScience 28 32650117
2019 OSBPL2 deficiency upregulate SQLE expression increasing intracellular cholesterol and cholesteryl ester by AMPK/SP1 and SREBF2 signalling pathway. Experimental cell research 28 31356817
2019 OSBPL2-disrupted pigs recapitulate dual features of human hearing loss and hypercholesterolaemia. Journal of genetics and genomics = Yi chuan xue bao 23 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 19 33854310
2024 Collagen I-induced VCAN/ERK signaling and PARP1/ZEB1-mediated metastasis facilitate OSBPL2 defect to promote colorectal cancer progression. Cell death & disease 18 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 14 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
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