Affinage

Showing OPTN — FIP2 is a alias.

OPTN

Optineurin · UniProt Q96CV9

Length
577 aa
Mass
65.9 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 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

OPTN (optineurin) is a multifunctional selective autophagy receptor that recognizes ubiquitin-decorated cargo and links cargo recognition to autophagosome biogenesis and innate immune signaling (PMID:26365381, PMID:32556086). Cargo recognition is mediated by its UBAN/ubiquitin-binding domain, whose crystal structure reveals preferential, asymmetric 2:1 binding to linear diubiquitin and whose disease-associated mutations abolish ubiquitin binding (PMID:29394115). TBK1 constitutively associates with OPTN, and OPTN ubiquitin-chain binding is required to recruit and activate TBK1 on cargo; activated TBK1 then phosphorylates OPTN at S177 (enhancing ATG8/LC3 recruitment) and at S473/S513 (expanding and strengthening ubiquitin-chain binding and promoting retention on damaged mitochondria), establishing a self-amplifying feedback loop (PMID:26365381, PMID:27035970). Beyond ATG8 binding, OPTN engages ATG9A vesicles to nucleate de novo autophagosomal membrane biogenesis directly at ubiquitinated cargo, defining an OPTN–ATG9A axis parallel to the CALCOCO2–RB1CC1 axis (PMID:32556086, PMID:32892694). Through these activities OPTN clears a broad substrate range, including PARKIN-tagged damaged mitochondria during mitophagy (PMID:25801386), aggregated huntingtin and TDP-43 inclusion bodies via K63-linked ubiquitin (PMID:25484089), damaged lysosomes (PMID:30404831), viral proteins targeted during HSV-1 and Seneca Valley virus infection (PMID:34518549, PMID:37930946), and metabolic substrates such as FABP3, ACSL4 and GCDH whose turnover depends on K63-linked ubiquitination (PMID:33143524, PMID:39875520, PMID:39099169). In parallel with its degradative role, OPTN dampens innate immune signaling by translocating to ATG9A-positive perinuclear foci that sequester LUBAC, CYLD and TBK1, restraining NF-κB and IRF3 activation (PMID:32376785), and by binding the RIPK1 death domain through its UBAN domain to promote RIPK1 ubiquitination and degradation (PMID:34861878). Disease-causing mutations act through distinct mechanisms: E478G and UBAN deletions disrupt ubiquitin binding and act as dominant-negative traps that impair autophagosome maturation and mitophagy (PMID:25801386, PMID:25484089); E50K drives autophagic-lysosomal degradation defects with reduced mTORC1 signaling in retinal ganglion cells (PMID:39425218); M98K promotes excessive transferrin-receptor autophagy and RAB12-dependent cell death (PMID:23357852); and a 2bp-insertion mutant constitutively activates TBK1 and induces ER-stress-dependent cell death (PMID:33548116), collectively linking OPTN dysfunction to glaucoma, ALS and neurodegeneration.

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2000 Medium

    Established OPTN (FIP-2) as a Rab8 effector and huntingtin-binding protein, the first clue that it operates at vesicular trafficking and aggregate-handling interfaces.

    Evidence Yeast two-hybrid and domain-mapping co-localization in mammalian cells

    PMID:11137014

    Open questions at the time
    • No demonstration of autophagy function
    • Interaction not validated in vitro with purified proteins
  2. 2002 Medium

    Defined the basal subcellular localization of OPTN at the Golgi, distinguishing structural from functional dependence using pharmacological disruption.

    Evidence Subcellular fractionation, immunofluorescence and nocodazole/brefeldin A perturbation in chicken ortholog

    PMID:12169269

    Open questions at the time
    • Chicken ortholog; human relevance inferred
    • Mechanism of Golgi targeting not defined
  3. 2015 High

    Showed OPTN is recruited to PARKIN-ubiquitinated mitochondria and drives autophagosome assembly via its LIR, and that the ALS mutation E478G abolishes this, directly tying ubiquitin binding to mitophagy and disease.

    Evidence High-resolution live-cell imaging with E478G loss-of-function in HeLa cells

    PMID:25801386

    Open questions at the time
    • Did not resolve TBK1 phosphoregulation
    • Membrane biogenesis mechanism not addressed
  4. 2015 Medium

    Demonstrated OPTN clears huntingtin/TDP-43 inclusion bodies via K63-ubiquitin-mediated autophagy and that UbBD mutants act as dominant-negative traps impairing MYO6/TOM1-dependent autophagosome maturation.

    Evidence Overexpression, co-IP, LC3 flux assays and inclusion-body isolation in Neuro2A cells

    PMID:25484089

    Open questions at the time
    • Largely overexpression-based
    • Endogenous flux contribution not quantified
  5. 2015 High

    Resolved the TBK1–OPTN feedback loop: TBK1 phosphorylates OPTN at S473/S513 to enhance ubiquitin binding and S177 to enhance ATG8 recruitment, with OPTN ubiquitin binding required for TBK1 activation.

    Evidence Quantitative phosphoproteomics, in vitro ubiquitin binding, mutagenesis and live-cell imaging

    PMID:26365381

    Open questions at the time
    • Structural basis of phospho-enhanced binding not resolved here
    • In vivo relevance not tested
  6. 2016 High

    Confirmed and extended the feedback model, showing constitutive TBK1–OPTN association, S473-dependent binding to pS65-ubiquitin chains, and a role in PINK1-driven Parkin-independent mitophagy.

    Evidence Quantitative proteomics, in vitro binding, mutagenesis and fluorescence microscopy

    PMID:27035970

    Open questions at the time
    • Parkin-independent pathway not fully reconstituted
    • Chain-type selectivity in cells incompletely mapped
  7. 2018 High

    Provided the structural basis of cargo recognition: OPTN UBAN preferentially binds linear ubiquitin in a 2:1 complex, with disease mutations disrupting binding and aggregate recruitment.

    Evidence Crystal structure, ITC, mutagenesis and co-localization imaging

    PMID:29394115

    Open questions at the time
    • Phospho-UBAN structure not solved
    • Selectivity over K63 chains in cells not fully reconciled
  8. 2020 High

    Identified OPTN–ATG9A interaction as a distinct membrane-biogenesis function beyond ATG8 binding, nucleating autophagosomal membranes at ubiquitinated mitochondria.

    Evidence Phase-separation foci assays, reciprocal co-IP, interaction mutants and chemically induced mitochondrial ubiquitination

    PMID:32556086

    Open questions at the time
    • Molecular geometry of ATG9A engagement unresolved
    • Lipid-source contribution not defined
  9. 2020 Medium

    Positioned the OPTN–ATG9A and CALCOCO2–RB1CC1 axes as two independent membrane-initiation routes on damaged mitochondria.

    Evidence Genetic epistasis with KO/rescue lines, co-IP and live-cell imaging

    PMID:32892694

    Open questions at the time
    • Limited additional experimental detail; largely extends prior work
    • Cross-talk between axes not quantified
  10. 2020 Medium

    Revealed OPTN as an immune brake that relocates to ATG9A-positive perinuclear foci to sequester LUBAC, CYLD and TBK1 and dampen NF-κB/IRF3 signaling, with glaucoma mutations causing aberrant constitutive foci.

    Evidence Live-cell imaging, BioID proximity proteomics, co-IP and cytokine assays

    PMID:32376785

    Open questions at the time
    • Whether sequestration requires autophagy is unclear
    • Endogenous foci dynamics not fully characterized
  11. 2018 Medium

    Extended OPTN/TBK1 function to lysosomal quality control, showing recruitment to alpha-synuclein-fibril-damaged ubiquitylated lysosomes with TBK1-dependent LC3 recruitment.

    Evidence Live-cell imaging, CLEM and TBK1 inhibition in microglial cells

    PMID:30404831

    Open questions at the time
    • Direct OPTN ubiquitin engagement on lysosomes not biochemically shown
    • In vivo relevance not tested
  12. 2021 High

    Demonstrated OPTN-mediated antiviral autophagy in vivo, targeting HSV-1 VP16 and gB for degradation and protecting against lethal CNS infection and necroptosis.

    Evidence OPTN-deficient mouse infection challenge, co-IP and necroptosis inhibitor rescue

    PMID:34518549

    Open questions at the time
    • Ubiquitin-tagging step on viral proteins not defined
    • Necroptosis link mechanistically incomplete
  13. 2021 Medium

    Showed OPTN restrains RIPK1-driven NF-κB inflammation via UBAN–death-domain binding promoting RIPK1 degradation, and limits AIM2 inflammasome activation.

    Evidence Co-IP, ectopic expression in BV2 cells and APP/PS1 mice, siRNA and ELISA

    PMID:34861878

    Open questions at the time
    • Direct vs indirect RIPK1 ubiquitination control unclear
    • AIM2 transcriptional mechanism undefined
  14. 2021 Medium

    Linked an ALS-associated 2bp-insertion mutant to constitutive TBK1 activation, ER stress and autophagy-dependent motor neuron death via nuclear mislocalization.

    Evidence Co-IP, localization imaging, TBK1/Atg5 knockdown and ER-stress inhibitor rescue in NSC-34 cells

    PMID:33548116

    Open questions at the time
    • Mechanism of nuclear mislocalization unknown
    • Endogenous mutant context not tested
  15. 2016 Medium

    Connected the ALS E478G mutation to aberrant NF-κB activation and in vivo neuroinflammation and neuronal death, supporting a gain-of-toxic-signaling component.

    Evidence Optn-/- MEFs, lentiviral motor-cortex overexpression, NF-κB reporters and cytokine ELISA

    PMID:30519240

    Open questions at the time
    • Overexpression-driven; physiological levels untested
    • Relationship to autophagy defect not integrated
  16. 2021 Medium

    Established functional redundancy of OPTN with p62 and Dram1 in antibacterial xenophagy, clarifying compensatory receptor logic.

    Evidence Single/double knockout and overexpression rescue in Mycobacterium-infected zebrafish

    PMID:38264729

    Open questions at the time
    • Molecular basis of compensation unresolved
    • Mammalian generalizability untested
  17. 2020 Medium

    Broadened OPTN substrate scope to metabolism by identifying FABP3 as a selective autophagy substrate whose accumulation drives bone loss in Optn-deficient mice.

    Evidence optn-/- mouse model with lentivirus rescue, MSC transplantation and FABP3 knockdown

    PMID:33143524

    Open questions at the time
    • FABP3 ubiquitin tag and receptor interface not mapped
    • Tissue specificity of substrate selection unclear
  18. 2023 High

    Identified OPTN as the sole non-redundant mitophagy receptor sustaining AML proliferation, revealing a context-dependent pro-survival role.

    Evidence Multiplexed CRISPR screen, respiration/ROS assays and murine transplantation model

    PMID:37439113

    Open questions at the time
    • Why redundancy is lost in AML is unexplained
    • Druggable dependency mechanism undefined
  19. 2023 Medium

    Showed Seneca Valley virus 3C protease cleaves OPTN at Q513 to disable VP1 autophagy and type I IFN signaling, defining a viral evasion strategy targeting OPTN.

    Evidence Co-IP, cleavage-site mapping, knockdown/overexpression and TBK1/IRF3 phosphorylation assays

    PMID:37930946

    Open questions at the time
    • Fragment fates in cells not fully characterized
    • In vivo relevance not tested
  20. 2024 Medium

    Extended OPTN substrate range to GCDH and showed VCP stabilizes BECN1 to boost OPTN-mediated mitophagy initiation, protecting against drug-induced liver injury.

    Evidence MS substrate ID, co-IP, microscale thermophoresis and OPTN-/- hepatocyte model

    PMID:39099169

    Open questions at the time
    • VCP–OPTN interface not structurally defined
    • Selectivity for GCDH unexplained
  21. 2024 Medium

    Demonstrated OPTN-mediated degradation of ACSL4 is gated by SUMO/ubiquitin cross-talk, with TRIM28/SUMO3 blocking and SENP3 restoring K63-ubiquitin-dependent OPTN recognition.

    Evidence Co-IP, MS modification-site mapping, mutagenesis and degradation assays

    PMID:39875520

    Open questions at the time
    • Direct OPTN–ACSL4 binding interface not defined
    • Physiological setting of regulation limited
  22. 2024 Medium

    Defined OPTN melanophagy: RCHY1-driven K63-ubiquitination recruits OPTN, which activates TBK1, and reciprocal TBK1 phosphorylation of OPTN at S187 is required for melanosome degradation.

    Evidence Knockdown, ubiquitin-linkage analysis, phosphorylation assays and live-cell imaging

    PMID:38536750

    Open questions at the time
    • S187 phosphosite role versus canonical sites unclear
    • In vivo melanophagy relevance untested
  23. 2024 Medium

    Linked the glaucoma E50K mutation to autophagic-lysosomal degradation failure with reduced mTORC1 signaling in human RGCs, and showed mTOR-independent autophagy induction rescues phenotypes.

    Evidence Isogenic hPSC-derived RGC CRISPR knock-in, flux assays, mTORC1 immunoblot and pharmacological rescue with in vivo validation

    PMID:39425218

    Open questions at the time
    • How E50K alters mTORC1/AMPK is mechanistically incomplete
    • Single isogenic system

Open questions

Synthesis pass · forward-looking unresolved questions
  • How OPTN integrates its degradative receptor activity with its immune-signaling brake at the molecular level, and how distinct disease mutations partition between loss of autophagy and gain of aberrant signaling, remains unresolved.
  • No unified structural model spanning UBAN, LIR, ATG9A and death-domain interfaces
  • Mutation-specific mechanisms not reconciled in a common cell system
  • Substrate-selection rules across diverse cargo not generalized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005739 mitochondrion 3 GO:0031410 cytoplasmic vesicle 3 GO:0005634 nucleus 1 GO:0005764 lysosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-168256 Immune System 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-162582 Signal Transduction 2
Partners
ATG9AMYO6RAB12RAB8RIPK1TBK1TOM1VCP

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 TBK1 physically associates with OPTN on damaged mitochondria and phosphorylates OPTN at S473 and S513, enhancing ubiquitin chain binding in vitro. TBK1 activation requires OPTN and NDP52 and OPTN ubiquitin chain binding. S177 phosphorylation promotes ATG8 recruitment; S473/S513 phosphorylation promotes ubiquitin chain binding and OPTN mitochondrial retention, creating a positive feedback loop for efficient mitophagy. Quantitative phosphoproteomics, in vitro ubiquitin binding assays, mutagenesis, live-cell imaging in HeLa cells, co-immunoprecipitation Molecular cell High 26365381
2016 TBK1 constitutively interacts with OPTN; OPTN's ubiquitin-chain binding is essential for TBK1 recruitment and kinase activation on mitochondria. TBK1 phosphorylates OPTN's UBAN domain at S473, expanding binding capacity to diverse ubiquitin chains. Combined phosphorylation at S177, S473, and S513 promotes retention of OPTN/TBK1 on ubiquitinated mitochondria. S473 phosphorylation also enables binding to pS65-ubiquitin chains and is implicated in PINK1-driven, Parkin-independent mitophagy. Quantitative proteomics, co-immunoprecipitation, in vitro ubiquitin binding assays, mutagenesis, live-cell fluorescence microscopy Proceedings of the National Academy of Sciences of the United States of America High 27035970
2018 The UBAN domain of OPTN preferentially recognizes linear ubiquitin chains and forms an asymmetric 2:1 stoichiometry complex with linear diubiquitin. Crystal structure revealed the interaction mode. TBK1-dependent phosphorylation of UBAN regulates ubiquitin-binding ability. Disease-associated mutations in the UBAN domain disrupt ubiquitin interaction, and defects in ubiquitin binding impair OPTN recruitment to linear ubiquitin-decorated huntingtin aggregates. Structural biology (crystal structure), isothermal titration calorimetry, mutagenesis, in vitro ubiquitin binding assays, co-localization imaging Autophagy High 29394115
2015 OPTN is recruited to ubiquitinated mitochondria downstream of PARKIN during mitophagy, and induces autophagosome assembly via its LC3-interacting region (LIR). The ALS-associated E478G mutation in OPTN's ubiquitin-binding domain causes defective mitophagy and accumulation of damaged mitochondria. High-resolution live-cell imaging, loss-of-function (E478G mutant expression), co-localization with ubiquitinated mitochondria Autophagy High 25801386
2020 OPTN forms a complex with ATG9A vesicles, and disruption of OPTN-ATG9A interactions abrogates mitophagy. This interaction is required for de novo synthesis of autophagosomal membranes near ubiquitinated mitochondria, functioning in addition to (not instead of) OPTN's ATG8-binding activity. Phase-separated fluorescent foci assays, co-immunoprecipitation, loss-of-function (OPTN-ATG9A interaction mutants), mitophagy induction by mitochondria-targeted ubiquitin chains The Journal of cell biology High 32556086
2020 OPTN-ATG9A and CALCOCO2-RB1CC1 define two distinct axes that independently initiate de novo autophagosomal membrane biogenesis on ubiquitin-coated damaged mitochondria, acting as scaffolds to build multivalent autophagy protein interactions near ubiquitinated cargo. Genetic epistasis using selective knockout and rescue experiments, co-immunoprecipitation, live-cell imaging Autophagy Medium 32892694
2015 OPTN's ubiquitin-binding domain (UbBD, amino acids 424-511) is required for colocalization with inclusion bodies formed by mutant huntingtin and TDP-43. Wild-type OPTN clears inclusion bodies via K63-linked polyubiquitin-mediated autophagy. UbBD mutants (E478G, UbBDΔ) act as dominant-negative traps by forming WT-mutant complexes, reducing interaction with MYO6 and TOM1, impairing autophagosome maturation and autophagic flux. Overexpression in Neuro2A cells, co-immunoprecipitation, LC3 flux assay, knockdown of autophagy components, IB isolation by sorting Autophagy Medium 25484089
2013 M98K-OPTN induces autophagosome-dependent death of retinal ganglion cells by promoting transferrin receptor delivery to autophagosomes for degradation. OPTN complexes with RAB12, and M98K-OPTN shows enhanced RAB12 colocalization. RAB12 knockdown increases transferrin receptor levels and reduces M98K-induced cell death; RAB12 is present in autophagosomes and required for autolysosome formation during starvation-induced autophagy. Co-immunoprecipitation, knockdown (shRNA), overexpression, LC3-II immunoblot, cell death assays in RGC-5 cells Autophagy Medium 23357852
2014 E50K-OPTN-induced retinal cell death requires the GTPase-activating protein TBC1D17 which inactivates Rab8. TBC1D17 localizes to autophagosomes and inhibits autophagy flux in a catalytically dependent manner. Knockdown of TBC1D17 rescues cells from E50K-OPTN-mediated autophagy flux inhibition and cell death. LC3-binding-defective E50K-OPTN shows reduced cell death, implicating autophagy in the mechanism. shRNA knockdown, catalytically inactive mutant expression, co-localization imaging, autophagy flux assays, cell death assays PloS one Medium 24752605
2018 Alpha-synuclein fibrils (but not monomers) induce lysosomal damage in microglial cells, recruiting TBK1 and OPTN to ubiquitylated damaged lysosomes. LC3 recruitment to damaged lysosomes is dependent on TBK1 activity. Autophagy inhibition under these conditions impairs mitochondrial function and leads to cell death, suggesting OPTN/TBK1-mediated autophagy serves lysosomal quality control. Live-cell imaging, correlative light-electron microscopy (CLEM), TBK1 inhibitor treatment, loss-of-function Journal of cell science Medium 30404831
2020 In response to viral RNA, OPTN translocates to perinuclear foci positive for ATG9A (small membrane vesicles) and negatively regulates NF-κB and IRF3 signaling and downstream pro-inflammatory cytokine secretion. OPTN sequesters LUBAC (linear ubiquitin assembly complex), CYLD, and TBK1 in this compartment. Glaucoma-associated OPTN disease mutations cause aberrant constitutive foci formation. Proximity-labeling proteomics identified the OPTN interactome at this compartment. Live-cell imaging, proximity-labeling proteomics (BioID), co-immunoprecipitation, loss-of-function, cytokine measurement Journal of cell science Medium 32376785
2021 OPTN selectively targets HSV-1 tegument protein VP16 and fusion glycoprotein gB for degradation via autophagy. OPTN-deficient mice show increased susceptibility to lethal CNS HSV-1 infection, cognitive decline, impaired adaptive immunity recruitment, and enhanced neuronal necroptosis. Ocular HSV-1 lethality without OPTN is rescued by a necroptosis inhibitor. OPTN-deficient mouse model, viral infection challenge, co-immunoprecipitation (OPTN with VP16 and gB), necroptosis inhibitor rescue Nature communications High 34518549
2020 OPTN functions as an autophagy receptor to clear FABP3 (fatty acid binding protein 3) via selective autophagy. OPTN deficiency in mice causes bone loss, elevated MSC senescence, decreased osteogenesis and enhanced adipogenesis. FABP3 was identified as a novel selective autophagy substrate of OPTN. FABP3 knockdown rescues bone loss in optn-/- mice. optn-/- mouse model, lentivirus rescue, loss-of-function mutant analysis, MSC transplantation, FABP3 knockdown Autophagy Medium 33143524
2021 OPTN suppresses RIPK1-mediated NF-κB inflammatory signaling via ubiquitin protease hydrolysis of RIPK1. The UBAN domain of OPTN binds the death domain (DD) of RIPK1 to facilitate its ubiquitination and degradation. OPTN also blocks AIM2 inflammasome activation by inhibiting AIM2 and ASC mRNA expression, reducing active caspase-1 and IL-1β. Co-immunoprecipitation, ectopic expression in BV2 cells and APP/PS1 mice, ELISA, immunofluorescence, siRNA knockdown Journal of neuroinflammation Medium 34861878
2022 TRIM14 inhibits OPTN-mediated selective autophagic degradation of the histone demethylase KDM4D. TRIM14 recruits deubiquitinases USP14 and BRCC3 to cleave K63-linked ubiquitin chains on KDM4D, preventing OPTN recognition and selective autophagy. TRIM14 deficiency in dendritic cells impairs KDM4D-directed expression of IL-12 and IL-23. Co-immunoprecipitation, deubiquitinase recruitment assays, K63-ubiquitin chain analysis, dendritic cell knockout, cytokine measurement Proceedings of the National Academy of Sciences of the United States of America Medium 35145029
2023 Seneca Valley virus 3C protease cleaves OPTN at glutamine 513, generating N-terminal and C-terminal fragments that have impaired selective autophagy of viral capsid protein VP1 and reduced type I IFN signaling. OPTN interacts with VP1 and targets it for degradation; the N-terminal fragment retains VP1 binding but has decreased degradation capacity. OPTN knockdown reduces TBK1 activation and IRF3 phosphorylation; overexpression increases TBK1-IRF3 signaling. Co-immunoprecipitation, protease cleavage site mapping, OPTN knockdown/overexpression, viral replication assays, TBK1/IRF3 phosphorylation measurement Autophagy Medium 37930946
2024 OPTN mediates selective autophagic degradation of ACSL4 via K63-linked ubiquitination. TRIM28-mediated SUMO3 modification of ACSL4 at K532 inhibits K63-linked ubiquitination and suppresses OPTN-dependent autophagic degradation of ACSL4. SENP3 reverses this by deSUMOylating ACSL4, restoring OPTN-mediated degradation. Co-immunoprecipitation, mass spectrometry, ubiquitination assays, SUMOylation site mutagenesis, OPTN knockdown, ACSL4 degradation assays Cell death and differentiation Medium 39875520
2024 OPTN mediates selective autophagic degradation of GCDH (glutaryl-CoA dehydrogenase) as a mitochondrial substrate. VCP (valosin containing protein) interacts with OPTN and stabilizes BECN1 during phagophore assembly, boosting OPTN-mediated mitophagy initiation. OPTN ablation causes disrupted mitochondrial homeostasis and aggravates hepatocyte necrosis in drug-induced liver injury. Mass spectrometry (substrate identification), co-immunoprecipitation, microscale thermophoresis, OPTN knockdown/overexpression, OPTN-/- mouse hepatocyte model Autophagy Medium 39099169
2024 In melanophagy, OPTN is recruited to melanosomes via its ubiquitin-binding domain after RCHY1 E3 ligase promotes K63-linked ubiquitination of melanosomes. OPTN activates TBK1, and subsequent TBK1-mediated phosphorylation of OPTN at S187 is essential for melanosome degradation. OPTN knockdown inhibits β-mangostin-mediated melanosome degradation. OPTN knockdown, RCHY1 knockdown, ubiquitin linkage analysis, TBK1 phosphorylation assays, domain deletion analysis, live-cell imaging Proceedings of the National Academy of Sciences of the United States of America Medium 38536750
2021 OPTN and p62 can compensate for each other's loss of function in xenophagy against Mycobacterium marinum in zebrafish. Dram1 can compensate for deficiencies in Optn and p62, and vice versa. optn/p62 double mutants show more severe infection susceptibility than single mutants. Overexpression of Optn restores Lc3 recruitment to mycobacteria in p62 mutant background. Single and double knockout zebrafish, overexpression rescue experiments, Lc3 colocalization with mycobacteria, infection susceptibility assays Frontiers in cellular and infection microbiology Medium 38264729
2000 FIP-2 (OPTN alias) was identified as a Rab8-interacting protein by yeast two-hybrid; the activated form of Rab8 interacted with the amino-terminal region of FIP-2, while dominant-negative Rab8 did not. Huntingtin bound to the carboxy-terminal region of FIP-2. Coexpressed FIP-2 and Huntingtin enhanced Huntingtin recruitment to Rab8-positive vesicular structures. FIP-2 promoted cell polarization similarly to Rab8. Yeast two-hybrid, co-localization imaging, domain mapping by deletion analysis Current biology : CB Medium 11137014
2002 Chicken FIP-2 (OPTN ortholog) concentrates at the Golgi apparatus in most cells. Nocodazole treatment (disrupting Golgi structure without loss of function) retains FIP-2 at dispersed Golgi fragments, while brefeldin A (disrupting Golgi structure and function) causes loss of FIP-2 from Golgi membranes. During erythroblast differentiation, FIP-2 translocates from the Golgi to the marginal band. Subcellular fractionation, immunofluorescence, pharmacological perturbation (nocodazole, brefeldin A), immunohistochemistry during differentiation Experimental cell research Medium 12169269
2016 The ALS-associated E478G mutation increases NF-κB activity in Optn-/- MEF cells. Lentiviral overexpression of OPTN E478G in mouse motor cortex significantly activates inflammation (increased pro-inflammatory cytokine secretion) and induces neuronal cell death in vivo. OPTN knockout MEF cells, lentiviral in vivo motor cortex injection, cytokine ELISA, NF-κB reporter assays, histological cell death analysis Frontiers in immunology Medium 30519240
2021 A 2bp insertion OPTN mutant (2bpIns-OPTN) localizes predominantly to the nucleus rather than cytoplasm. It interacts with TBK1 but not with wild-type OPTN and constitutively activates TBK1. This mutant induces ER stress (CHOP induction), impairs autophagy (LC3-II accumulation), and causes cell death in NSC-34 motor neuron cells; all effects were abrogated by TBK1 knockdown or ER stress inhibitor 4-phenylbutyric acid. Atg5 knockdown blocked CHOP induction and cell death. Co-immunoprecipitation, nuclear localization imaging, TBK1 knockdown, siRNA Atg5 knockdown, ER stress marker immunoblot, autophagy flux assays, cell death assays The FEBS journal Medium 33548116
2023 OPTN is the sole non-redundant mitophagy receptor in AML cells identified by pairwise multiplexed CRISPR screen. OPTN expression is rate-limiting for AML cell proliferation; OPTN loss impairs mitochondrial respiration and increases mitochondrial ROS. In a MN1-driven murine transplantation model, OPTN loss prolonged median survival by 21%. Multiplexed CRISPR screen, OPTN knockdown/overexpression, mitochondrial respiration assays (Seahorse), ROS measurement, murine transplantation model Autophagy High 37439113
2024 OPTN(E50K) mutation in hPSC-derived RGCs causes impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via AMPK activation, leading to neurodegeneration. Pharmacological mTORC1 inhibition in healthy RGCs recapitulates disease phenotypes; mTOR-independent autophagy induction reduces protein accumulation and restores neurite outgrowth in OPTN(E50K) RGCs. hPSC-derived RGC isogenic model, CRISPR E50K knock-in, autophagy flux assays, mTORC1 signaling immunoblot, pharmacological rescue (rapamycin and mTOR-independent inducers), ocular hypertension mouse model validation Acta neuropathologica communications Medium 39425218

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The PINK1-PARKIN Mitochondrial Ubiquitylation Pathway Drives a Program of OPTN/NDP52 Recruitment and TBK1 Activation to Promote Mitophagy. Molecular cell 738 26365381
2016 Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proceedings of the National Academy of Sciences of the United States of America 613 27035970
2015 Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta neuropathologica 263 25943890
2000 FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis. Current biology : CB 183 11137014
2020 Critical role of mitochondrial ubiquitination and the OPTN-ATG9A axis in mitophagy. The Journal of cell biology 165 32556086
2005 Interactions between EHD proteins and Rab11-FIP2: a role for EHD3 in early endosomal transport. Molecular biology of the cell 160 16251358
2015 Mutations in the ubiquitin-binding domain of OPTN/optineurin interfere with autophagy-mediated degradation of misfolded proteins by a dominant-negative mechanism. Autophagy 141 25484089
2020 Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing FABP3. Autophagy 127 33143524
2008 Respiratory syncytial virus uses a Vps4-independent budding mechanism controlled by Rab11-FIP2. Proceedings of the National Academy of Sciences of the United States of America 127 18621683
2021 Emerging views of OPTN (optineurin) function in the autophagic process associated with disease. Autophagy 110 33783320
2006 A Role of myosin Vb and Rab11-FIP2 in the aquaporin-2 shuttle. Traffic (Copenhagen, Denmark) 110 17156409
2002 Rab11-FIP2 functions in transferrin recycling and associates with endosomal membranes via its COOH-terminal domain. The Journal of biological chemistry 99 11994279
2015 Temporal dynamics of PARK2/parkin and OPTN/optineurin recruitment during the mitophagy of damaged mitochondria. Autophagy 98 25801386
2018 Structural insights into the ubiquitin recognition by OPTN (optineurin) and its regulation by TBK1-mediated phosphorylation. Autophagy 96 29394115
2002 Rab11-FIP2, an adaptor protein connecting cellular components involved in internalization and recycling of epidermal growth factor receptors. The Journal of biological chemistry 85 12364336
2013 M98K-OPTN induces transferrin receptor degradation and RAB12-mediated autophagic death in retinal ganglion cells. Autophagy 79 23357852
2020 Retinal Ganglion Cells With a Glaucoma OPTN(E50K) Mutation Exhibit Neurodegenerative Phenotypes when Derived from Three-Dimensional Retinal Organoids. Stem cell reports 74 32531194
2012 Screening of the SOD1, FUS, TARDBP, ANG, and OPTN mutations in Korean patients with familial and sporadic ALS. Neurobiology of aging 74 22244934
2011 Screening of OPTN in French familial amyotrophic lateral sclerosis. Neurobiology of aging 68 21220178
2007 Role of CYP1B1, MYOC, OPTN, and OPTC genes in adult-onset primary open-angle glaucoma: predominance of CYP1B1 mutations in Indian patients. Molecular vision 68 17563717
2014 Rab11-FIP2 interaction with MYO5B regulates movement of Rab11a-containing recycling vesicles. Traffic (Copenhagen, Denmark) 57 24372966
2009 Requirement of myosin Vb.Rab11a.Rab11-FIP2 complex in cholesterol-regulated translocation of NPC1L1 to the cell surface. The Journal of biological chemistry 57 19542231
2018 Alpha-synuclein fibrils recruit TBK1 and OPTN to lysosomal damage sites and induce autophagy in microglial cells. Journal of cell science 55 30404831
2014 E50K-OPTN-induced retinal cell death involves the Rab GTPase-activating protein, TBC1D17 mediated block in autophagy. PloS one 55 24752605
2021 OPTN is a host intrinsic restriction factor against neuroinvasive HSV-1 infection. Nature communications 53 34518549
2007 Variation in optineurin (OPTN) allele frequencies between and within populations. Molecular vision 52 17293779
2011 Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS. Neurobiology of aging 47 21852022
2010 The majority of the genetic risk for Paget's disease of bone is explained by genetic variants close to the CSF1, OPTN, TM7SF4, and TNFRSF11A genes. Human genetics 47 20839008
2006 OPTN gene: profile of patients with glaucoma from India. Molecular vision 46 16885925
2010 Analysis of OPTN as a causative gene for amyotrophic lateral sclerosis. Neurobiology of aging 44 21074290
2016 Rab11-FIP2 promotes colorectal cancer migration and invasion by regulating PI3K/AKT/MMP7 signaling pathway. Biochemical and biophysical research communications 43 26792722
2018 Detection of mutations in MYOC, OPTN, NTF4, WDR36 and CYP1B1 in Chinese juvenile onset open-angle glaucoma using exome sequencing. Scientific reports 42 29540704
2016 OPTN 691_692insAG is a founder mutation causing recessive ALS and increased risk in heterozygotes. Neurology 41 26740678
2021 Downregulating expression of OPTN elevates neuroinflammation via AIM2 inflammasome- and RIPK1-activating mechanisms in APP/PS1 transgenic mice. Journal of neuroinflammation 40 34861878
2012 A Rab11A/myosin Vb/Rab11-FIP2 complex frames two late recycling steps of langerin from the ERC to the plasma membrane. Traffic (Copenhagen, Denmark) 40 22420646
2020 Two different axes CALCOCO2-RB1CC1 and OPTN-ATG9A initiate PRKN-mediated mitophagy. Autophagy 38 32892694
2021 A glaucoma- and ALS-associated mutant of OPTN induces neuronal cell death dependent on Tbk1 activity, autophagy and ER stress. The FEBS journal 37 33548116
2018 ALS-Associated E478G Mutation in Human OPTN (Optineurin) Promotes Inflammation and Induces Neuronal Cell Death. Frontiers in immunology 37 30519240
2021 iTRAQ-Based Quantitative Proteomics Indicated Nrf2/OPTN-Mediated Mitophagy Inhibits NLRP3 Inflammasome Activation after Intracerebral Hemorrhage. Oxidative medicine and cellular longevity 35 33628368
2022 Astrocytes modulate neurodegenerative phenotypes associated with glaucoma in OPTN(E50K) human stem cell-derived retinal ganglion cells. Stem cell reports 34 35714595
2012 Novel deletion mutations of OPTN in amyotrophic lateral sclerosis in Japanese. Neurobiology of aging 34 22402017
2020 OPTN recruitment to a Golgi-proximal compartment regulates immune signalling and cytokine secretion. Journal of cell science 33 32376785
2015 Oligogenic inheritance of optineurin (OPTN) and C9ORF72 mutations in ALS highlights localisation of OPTN in the TDP-43-negative inclusions of C9ORF72-ALS. Neuropathology : official journal of the Japanese Society of Neuropathology 33 26303227
2003 The role of TIGR and OPTN in Finnish glaucoma families: a clinical and molecular genetic study. Molecular vision 33 12789137
2020 Sorting Rare ALS Genetic Variants by Targeted Re-Sequencing Panel in Italian Patients: OPTN, VCP, and SQSTM1 Variants Account for 3% of Rare Genetic Forms. Journal of clinical medicine 31 32028661
2025 Redox regulation of TRIM28 facilitates neuronal ferroptosis by promoting SUMOylation and inhibiting OPTN-selective autophagic degradation of ACSL4. Cell death and differentiation 30 39875520
2023 Seneca Valley virus 3C protease cleaves OPTN (optineurin) to Impair selective autophagy and type I interferon signaling. Autophagy 30 37930946
2007 Role of MYOC and OPTN sequence variations in Spanish patients with primary open-angle glaucoma. Molecular vision 30 17615537
2012 Phosphorylation of Rab11-FIP2 regulates polarity in MDCK cells. Molecular biology of the cell 29 22553350
2007 Rab11-FIP2 regulates differentiable steps in transcytosis. American journal of physiology. Cell physiology 29 17626244
2022 TRIM14 inhibits OPTN-mediated autophagic degradation of KDM4D to epigenetically regulate inflammation. Proceedings of the National Academy of Sciences of the United States of America 28 35145029
2016 A novel amyotrophic lateral sclerosis mutation in OPTN induces ER stress and Golgi fragmentation in vitro. Amyotrophic lateral sclerosis & frontotemporal degeneration 28 27534431
2015 Rab11-FIP2 promotes the metastasis of gastric cancer cells. International journal of cancer 27 26502090
2022 Age-related visual impairments and retinal ganglion cells axonal degeneration in a mouse model harboring OPTN (E50K) mutation. Cell death & disease 24 35436991
2022 OPTN attenuates the neurotoxicity of abnormal Tau protein by restoring autophagy. Translational psychiatry 24 35662233
2013 Validation of organ procurement and transplant network (OPTN)/united network for organ sharing (UNOS) criteria for imaging diagnosis of hepatocellular carcinoma. Transplantation 24 23778569
2007 FIP2 and Rip11 specify Rab11a-mediated cellular distribution of GLUT4 and FAT/CD36 in H9c2-hIR cells. Biochemical and biophysical research communications 24 17854769
2020 Lysosomal degradation of depolarized mitochondria is rate-limiting in OPTN-dependent neuronal mitophagy. Autophagy 22 32131674
2017 Acquisition of Rab11 and Rab11-Fip2-A novel strategy for Chlamydia pneumoniae early survival. PLoS pathogens 22 28787457
2011 Rab11-FIP2 influences multiple components of the endosomal system in polarized MDCK cells. Cellular logistics 22 21686255
2004 Analysis of optineurin (OPTN) gene mutations in subjects with and without glaucoma: the Blue Mountains Eye Study. Clinical & experimental ophthalmology 22 15498064
2018 Inhibition of the miR-192/215-Rab11-FIP2 axis suppresses human gastric cancer progression. Cell death & disease 21 30006518
2011 Screening for OPTN mutations in amyotrophic lateral sclerosis in a mainly Caucasian population. Neurobiology of aging 20 21550138
2023 A glaucoma-associated OPTN polymorphism, M98K sensitizes retinal cells to endoplasmic reticulum stress and tumour necrosis factor α. The FEBS journal 19 36705529
2017 Effect of genetic variants of OPTN in the pathophysiology of Paget's disease of bone. Biochimica et biophysica acta. Molecular basis of disease 19 28993189
2024 Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent Mitophagy. Autophagy 18 39099169
2018 Identification of compound heterozygous variants in OPTN in an ALS-FTD patient from the CReATe consortium: a case report. Amyotrophic lateral sclerosis & frontotemporal degeneration 18 29558868
2012 Genetic association study of UCMA/GRP and OPTN genes (PDB6 locus) with Paget's disease of bone. Bone 18 22796589
2002 FIP-2, an IkappaB-kinase-gamma-related protein, is associated with the Golgi apparatus and translocates to the marginal band during chicken erythroblast differentiation. Experimental cell research 18 12169269
2023 Deciphering the mitophagy receptor network identifies a crucial role for OPTN (optineurin) in acute myeloid leukemia. Autophagy 17 37439113
2012 Mutational analysis of familial and sporadic amyotrophic lateral sclerosis with OPTN mutations in Japanese population. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 17 22708870
2006 Molecular dissection of Rab11 binding from coiled-coil formation in the Rab11-FIP2 C-terminal domain. Biochemistry 17 16734419
2021 Proteomic analysis of aged and OPTN E50K retina in the development of normal tension glaucoma. Human molecular genetics 16 33856034
2021 Neuroprotective effects of bone marrow Sca-1+ cells against age-related retinal degeneration in OPTN E50K mice. Cell death & disease 16 34127652
2020 Respiratory pathology in the Optn-/- mouse model of Amyotrophic Lateral Sclerosis. Respiratory physiology & neurobiology 16 32805420
2018 Rab11-FIP2 suppressed tumor growth via regulation of PGK1 ubiquitination in non-small cell lung cancer. Biochemical and biophysical research communications 16 30471866
2017 OPTN p.Met468Arg and ATXN2 intermediate length polyQ extension in families with C9orf72 mediated amyotrophic lateral sclerosis and frontotemporal dementia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 16 29080331
2012 Screening for OPTN mutations in a cohort of British amyotrophic lateral sclerosis patients. Neurobiology of aging 16 22892313
2022 OPTN (optineurin)-mediated selective autophagy prevents neurodegeneration due to herpesvirus infection. Autophagy 15 35167411
2023 OPTN gene therapy increases autophagy and protects mitochondria in SOD1-G93A-expressing transgenic mice and cells. The FEBS journal 13 37983563
2022 Baicalein Activates Parkin-Dependent Mitophagy through NDP52 and OPTN. Cells 13 35406696
2018 Overexpression of Rab11-FIP2 in colorectal cancer cells promotes tumor migration and angiogenesis through increasing secretion of PAI-1. Cancer cell international 13 29540997
2024 SENP1 facilitates OM-MSC differentiation through activating OPTN-mediated mitophagy to mitigate the neurologic impairment following ICH. iScience 12 38770132
2022 OPTN variants in ALS cases: a case report of a novel mutation and literature review. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 12 35661277
2013 Structural and functional analysis of FIP2 binding to the endosome-localised Rab25 GTPase. Biochimica et biophysica acta 12 24056041
2021 Outcomes of Kidney Transplant Recipients with Sickle Cell Disease: An Analysis of the 2000-2019 UNOS/OPTN Database. Journal of clinical medicine 11 34300230
2019 Renal cell carcinoma suspected at time of organ donation 2008-2016: A report of the OPTN ad hoc Disease Transmission Advisory Committee Registry. Clinical transplantation 11 31104323
2018 Molecular effect of an OPTN common variant associated to Paget's disease of bone. PloS one 11 29782529
2015 Identification of an Alu-repeat-mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype. Molecular genetics & genomic medicine 11 26740941
2024 Xenophagy receptors Optn and p62 and autophagy modulator Dram1 independently promote the zebrafish host defense against Mycobacterium marinum. Frontiers in cellular and infection microbiology 10 38264729
2008 Absence of optineurin (OPTN) gene mutations in Taiwanese patients with juvenile-onset open-angle glaucoma. Molecular vision 9 18385781
2024 RCHY1 and OPTN are required for melanophagy, selective autophagy of melanosomes. Proceedings of the National Academy of Sciences of the United States of America 8 38536750
2024 Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations. Alzheimer's research & therapy 8 38872230
2021 Human primary retinal cells as an in-vitro model for investigating defective signalling caused by OPTN mutants associated with glaucoma. Neurochemistry international 8 34023378
2006 Purification, crystallization and preliminary X-ray diffraction studies of Rab11 in complex with Rab11-FIP2. Acta crystallographica. Section F, Structural biology and crystallization communications 8 16820696
2005 Purification and functional properties of Rab11-FIP2. Methods in enzymology 8 16473614
2024 Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction. Acta neuropathologica communications 7 39425218
2016 Decreased expression of miR‑9 due to E50K OPTN mutation causes disruption of the expression of BDNF leading to RGC‑5 cell apoptosis. Molecular medicine reports 7 27748809
2022 Neutralizing peripheral circulating IL1β slows the progression of ALS in a lentivirus-infected OPTNE478G mouse model. Animal models and experimental medicine 6 36575589
2022 Gefitinib facilitates PINK1/Parkin-mediated mitophagy by enhancing mitochondrial recruitment of OPTN. Fundamental research 6 38933121

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