{"gene":"OPTN","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2015,"finding":"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.","method":"Quantitative phosphoproteomics, in vitro ubiquitin binding assays, mutagenesis, live-cell imaging in HeLa cells, co-immunoprecipitation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitin binding assays with mutagenesis, quantitative proteomics, live-cell imaging, replicated by independent lab (PMID:27035970)","pmids":["26365381"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Quantitative proteomics, co-immunoprecipitation, in vitro ubiquitin binding assays, mutagenesis, live-cell fluorescence microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — quantitative phosphoproteomics with multiple orthogonal methods (in vitro binding, mutagenesis, imaging); independently replicates and extends PMID:26365381","pmids":["27035970"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Structural biology (crystal structure), isothermal titration calorimetry, mutagenesis, in vitro ubiquitin binding assays, co-localization imaging","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation by mutagenesis and in vitro binding assays in single study","pmids":["29394115"],"is_preprint":false},{"year":2015,"finding":"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.","method":"High-resolution live-cell imaging, loss-of-function (E478G mutant expression), co-localization with ubiquitinated mitochondria","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell imaging with functional mutagenesis, replicated across multiple studies","pmids":["25801386"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Phase-separated fluorescent foci assays, co-immunoprecipitation, loss-of-function (OPTN-ATG9A interaction mutants), mitophagy induction by mitochondria-targeted ubiquitin chains","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mutant rescue experiments, novel chemical-induced ubiquitination tools, single lab with multiple orthogonal methods","pmids":["32556086"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Genetic epistasis using selective knockout and rescue experiments, co-immunoprecipitation, live-cell imaging","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple KO lines; largely a commentary/extension of PMID:32556086 with limited additional experimental detail in abstract","pmids":["32892694"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Overexpression in Neuro2A cells, co-immunoprecipitation, LC3 flux assay, knockdown of autophagy components, IB isolation by sorting","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional readouts, mutagenesis, autophagy flux assays; single lab with multiple methods","pmids":["25484089"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation, knockdown (shRNA), overexpression, LC3-II immunoblot, cell death assays in RGC-5 cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, shRNA knockdown with specific phenotypic readouts; single lab, multiple methods","pmids":["23357852"],"is_preprint":false},{"year":2014,"finding":"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.","method":"shRNA knockdown, catalytically inactive mutant expression, co-localization imaging, autophagy flux assays, cell death assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with rescue, catalytic mutants, multiple readouts; single lab","pmids":["24752605"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Live-cell imaging, correlative light-electron microscopy (CLEM), TBK1 inhibitor treatment, loss-of-function","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLEM, pharmacological inhibition with functional readouts; single lab","pmids":["30404831"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Live-cell imaging, proximity-labeling proteomics (BioID), co-immunoprecipitation, loss-of-function, cytokine measurement","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity proteomics with co-IP validation and functional signaling readouts; single lab, multiple orthogonal methods","pmids":["32376785"],"is_preprint":false},{"year":2021,"finding":"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.","method":"OPTN-deficient mouse model, viral infection challenge, co-immunoprecipitation (OPTN with VP16 and gB), necroptosis inhibitor rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model, co-IP substrate identification, pharmacological rescue; multiple orthogonal methods","pmids":["34518549"],"is_preprint":false},{"year":2020,"finding":"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.","method":"optn-/- mouse model, lentivirus rescue, loss-of-function mutant analysis, MSC transplantation, FABP3 knockdown","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with rescue experiments, novel substrate identification; single lab, multiple methods","pmids":["33143524"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, ectopic expression in BV2 cells and APP/PS1 mice, ELISA, immunofluorescence, siRNA knockdown","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, in vivo mouse model, siRNA knockdown with specific signaling readouts; single lab","pmids":["34861878"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, deubiquitinase recruitment assays, K63-ubiquitin chain analysis, dendritic cell knockout, cytokine measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitin chain analysis, KO with functional cytokine readouts; single lab, multiple methods","pmids":["35145029"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, protease cleavage site mapping, OPTN knockdown/overexpression, viral replication assays, TBK1/IRF3 phosphorylation measurement","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP substrate identification, cleavage site determination, signaling readouts; single lab","pmids":["37930946"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, mass spectrometry, ubiquitination assays, SUMOylation site mutagenesis, OPTN knockdown, ACSL4 degradation assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, MS identification of modification sites, mutagenesis, knockdown with degradation readouts; single lab","pmids":["39875520"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Mass spectrometry (substrate identification), co-immunoprecipitation, microscale thermophoresis, OPTN knockdown/overexpression, OPTN-/- mouse hepatocyte model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS substrate ID, co-IP, MST binding assay, knockout model; single lab, multiple methods","pmids":["39099169"],"is_preprint":false},{"year":2024,"finding":"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.","method":"OPTN knockdown, RCHY1 knockdown, ubiquitin linkage analysis, TBK1 phosphorylation assays, domain deletion analysis, live-cell imaging","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown, ubiquitin chain analysis, phosphorylation assays; single lab, multiple orthogonal methods","pmids":["38536750"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Single and double knockout zebrafish, overexpression rescue experiments, Lc3 colocalization with mycobacteria, infection susceptibility assays","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double knockout epistasis in zebrafish, overexpression rescue with Lc3 functional readout; single lab","pmids":["38264729"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Yeast two-hybrid, co-localization imaging, domain mapping by deletion analysis","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid with domain mapping and co-localization; replicated interaction context but limited in vitro validation","pmids":["11137014"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Subcellular fractionation, immunofluorescence, pharmacological perturbation (nocodazole, brefeldin A), immunohistochemistry during differentiation","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with pharmacological perturbations and differentiation-linked translocation; single lab, chicken ortholog","pmids":["12169269"],"is_preprint":false},{"year":2016,"finding":"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.","method":"OPTN knockout MEF cells, lentiviral in vivo motor cortex injection, cytokine ELISA, NF-κB reporter assays, histological cell death analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo lentiviral model with multiple cytokine readouts; single lab","pmids":["30519240"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, nuclear localization imaging, TBK1 knockdown, siRNA Atg5 knockdown, ER stress marker immunoblot, autophagy flux assays, cell death assays","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional rescue by knockdown and pharmacological inhibition; single lab, multiple methods","pmids":["33548116"],"is_preprint":false},{"year":2023,"finding":"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%.","method":"Multiplexed CRISPR screen, OPTN knockdown/overexpression, mitochondrial respiration assays (Seahorse), ROS measurement, murine transplantation model","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen for epistasis, in vivo transplantation model, mitochondrial function assays; multiple orthogonal methods","pmids":["37439113"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic human cell model with pharmacological rescue and in vivo validation; single lab","pmids":["39425218"],"is_preprint":false}],"current_model":"OPTN (optineurin) functions as a multifunctional selective autophagy receptor that recognizes ubiquitin-decorated cargo (mitochondria, protein aggregates, lysosomes, viral proteins, melanosomes, and other substrates) via its UBAN domain, which preferentially binds linear ubiquitin chains; TBK1 constitutively associates with OPTN and, upon ubiquitin-chain-triggered recruitment to cargo, phosphorylates OPTN at S177 (enhancing LC3/ATG8 binding), S473, and S513 (enhancing ubiquitin-chain binding and mitochondrial retention) in a self-amplifying positive feedback loop; beyond ATG8 binding, OPTN also interacts directly with ATG9A vesicles to nucleate de novo autophagosomal membrane biogenesis at ubiquitinated cargo; OPTN additionally dampens NF-κB and IRF3 signaling by sequestering LUBAC and other positive regulators in an ATG9A-positive perinuclear compartment, and facilitates RIPK1 ubiquitination and degradation via its UBAN-death domain interaction; disease-causing mutations (E50K, E478G, M98K, 2bpIns) variously disrupt ubiquitin binding, dominant-negatively impair autophagosome maturation through MYO6/TOM1 interactions, constitutively activate TBK1, or aberrantly activate NF-κB, linking OPTN dysfunction to glaucoma, ALS, and neurodegeneration."},"narrative":{"mechanistic_narrative":"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.","teleology":[{"year":2000,"claim":"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","pmids":["11137014"],"confidence":"Medium","gaps":["No demonstration of autophagy function","Interaction not validated in vitro with purified proteins"]},{"year":2002,"claim":"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","pmids":["12169269"],"confidence":"Medium","gaps":["Chicken ortholog; human relevance inferred","Mechanism of Golgi targeting not defined"]},{"year":2015,"claim":"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","pmids":["25801386"],"confidence":"High","gaps":["Did not resolve TBK1 phosphoregulation","Membrane biogenesis mechanism not addressed"]},{"year":2015,"claim":"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","pmids":["25484089"],"confidence":"Medium","gaps":["Largely overexpression-based","Endogenous flux contribution not quantified"]},{"year":2015,"claim":"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","pmids":["26365381"],"confidence":"High","gaps":["Structural basis of phospho-enhanced binding not resolved here","In vivo relevance not tested"]},{"year":2016,"claim":"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","pmids":["27035970"],"confidence":"High","gaps":["Parkin-independent pathway not fully reconstituted","Chain-type selectivity in cells incompletely mapped"]},{"year":2018,"claim":"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","pmids":["29394115"],"confidence":"High","gaps":["Phospho-UBAN structure not solved","Selectivity over K63 chains in cells not fully reconciled"]},{"year":2020,"claim":"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","pmids":["32556086"],"confidence":"High","gaps":["Molecular geometry of ATG9A engagement unresolved","Lipid-source contribution not defined"]},{"year":2020,"claim":"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","pmids":["32892694"],"confidence":"Medium","gaps":["Limited additional experimental detail; largely extends prior work","Cross-talk between axes not quantified"]},{"year":2020,"claim":"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","pmids":["32376785"],"confidence":"Medium","gaps":["Whether sequestration requires autophagy is unclear","Endogenous foci dynamics not fully characterized"]},{"year":2018,"claim":"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","pmids":["30404831"],"confidence":"Medium","gaps":["Direct OPTN ubiquitin engagement on lysosomes not biochemically shown","In vivo relevance not tested"]},{"year":2021,"claim":"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","pmids":["34518549"],"confidence":"High","gaps":["Ubiquitin-tagging step on viral proteins not defined","Necroptosis link mechanistically incomplete"]},{"year":2021,"claim":"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","pmids":["34861878"],"confidence":"Medium","gaps":["Direct vs indirect RIPK1 ubiquitination control unclear","AIM2 transcriptional mechanism undefined"]},{"year":2021,"claim":"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","pmids":["33548116"],"confidence":"Medium","gaps":["Mechanism of nuclear mislocalization unknown","Endogenous mutant context not tested"]},{"year":2016,"claim":"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","pmids":["30519240"],"confidence":"Medium","gaps":["Overexpression-driven; physiological levels untested","Relationship to autophagy defect not integrated"]},{"year":2021,"claim":"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","pmids":["38264729"],"confidence":"Medium","gaps":["Molecular basis of compensation unresolved","Mammalian generalizability untested"]},{"year":2020,"claim":"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","pmids":["33143524"],"confidence":"Medium","gaps":["FABP3 ubiquitin tag and receptor interface not mapped","Tissue specificity of substrate selection unclear"]},{"year":2023,"claim":"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","pmids":["37439113"],"confidence":"High","gaps":["Why redundancy is lost in AML is unexplained","Druggable dependency mechanism undefined"]},{"year":2023,"claim":"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","pmids":["37930946"],"confidence":"Medium","gaps":["Fragment fates in cells not fully characterized","In vivo relevance not tested"]},{"year":2024,"claim":"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","pmids":["39099169"],"confidence":"Medium","gaps":["VCP–OPTN interface not structurally defined","Selectivity for GCDH unexplained"]},{"year":2024,"claim":"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","pmids":["39875520"],"confidence":"Medium","gaps":["Direct OPTN–ACSL4 binding interface not defined","Physiological setting of regulation limited"]},{"year":2024,"claim":"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","pmids":["38536750"],"confidence":"Medium","gaps":["S187 phosphosite role versus canonical sites unclear","In vivo melanophagy relevance untested"]},{"year":2024,"claim":"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","pmids":["39425218"],"confidence":"Medium","gaps":["How E50K alters mTORC1/AMPK is mechanistically incomplete","Single isogenic system"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,13]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[21]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,3,17]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4,10,20]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,3,4,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,11,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3,17,24]}],"complexes":[],"partners":["TBK1","ATG9A","RIPK1","MYO6","TOM1","RAB8","RAB12","VCP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96CV9","full_name":"Optineurin","aliases":["E3-14.7K-interacting protein","FIP-2","Huntingtin yeast partner L","Huntingtin-interacting protein 7","HIP-7","Huntingtin-interacting protein L","NEMO-related protein","Optic 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Links myosin VI to the Golgi complex and plays an important role in Golgi ribbon formation (PubMed:27534431). Plays a role in the activation of innate immune response during viral infection. Mechanistically, recruits TBK1 at the Golgi apparatus, promoting its trans-phosphorylation after RLR or TLR3 stimulation (PubMed:27538435). In turn, activated TBK1 phosphorylates its downstream partner IRF3 to produce IFN-beta/IFNB1. Plays a neuroprotective role in the eye and optic nerve. May act by regulating membrane trafficking and cellular morphogenesis via a complex that contains Rab8 and huntingtin (HD). Mediates the interaction of Rab8 with the probable GTPase-activating protein TBC1D17 during Rab8-mediated endocytic trafficking, such as that of transferrin receptor (TFRC/TfR); regulates Rab8 recruitment to tubules emanating from the endocytic recycling compartment (PubMed:22854040). Autophagy receptor that interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family; targets ubiquitin-coated bacteria (xenophagy), such as cytoplasmic Salmonella enterica, and appears to function in the same pathway as SQSTM1 and CALCOCO2/NDP52 (Microbial infection) May constitute a cellular target for various viruses, such as adenovirus E3 14.7 or Bluetongue virus, to inhibit innate immune response (PubMed:27538435, PubMed:9488477). During RNA virus infection, such as that of Sendai virus, negatively regulates the induction of IFNB1 (PubMed:20174559)","subcellular_location":"Cytoplasm, perinuclear region; Golgi apparatus; Golgi apparatus, trans-Golgi network; Cytoplasmic vesicle, autophagosome; Cytoplasmic vesicle; Recycling endosome","url":"https://www.uniprot.org/uniprotkb/Q96CV9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OPTN","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/OPTN","total_profiled":1310},"omim":[{"mim_id":"619132","title":"FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 8; FTDALS8","url":"https://www.omim.org/entry/619132"},{"mim_id":"616659","title":"TBC1 DOMAIN FAMILY, MEMBER 17; TBC1D17","url":"https://www.omim.org/entry/616659"},{"mim_id":"616439","title":"FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 4; FTDALS4","url":"https://www.omim.org/entry/616439"},{"mim_id":"616437","title":"FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 3; FTDALS3","url":"https://www.omim.org/entry/616437"},{"mim_id":"613435","title":"AMYOTROPHIC LATERAL SCLEROSIS 12 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS12","url":"https://www.omim.org/entry/613435"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":835.6},{"tissue":"tongue","ntpm":368.6}],"url":"https://www.proteinatlas.org/search/OPTN"},"hgnc":{"alias_symbol":["FIP2","HYPL","FIP-2","TFIIIA-INTP","NRP","HIP7"],"prev_symbol":["GLC1E"]},"alphafold":{"accession":"Q96CV9","domains":[{"cath_id":"1.20.5","chopping":"39-111","consensus_level":"medium","plddt":95.3595,"start":39,"end":111},{"cath_id":"1.20.5","chopping":"439-521","consensus_level":"medium","plddt":92.852,"start":439,"end":521}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CV9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CV9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CV9-F1-predicted_aligned_error_v6.png","plddt_mean":77.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OPTN","jax_strain_url":"https://www.jax.org/strain/search?query=OPTN"},"sequence":{"accession":"Q96CV9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96CV9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96CV9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CV9"}},"corpus_meta":[{"pmid":"26365381","id":"PMC_26365381","title":"The 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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.\",\n      \"method\": \"Quantitative phosphoproteomics, in vitro ubiquitin binding assays, mutagenesis, live-cell imaging in HeLa cells, co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitin binding assays with mutagenesis, quantitative proteomics, live-cell imaging, replicated by independent lab (PMID:27035970)\",\n      \"pmids\": [\"26365381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Quantitative proteomics, co-immunoprecipitation, in vitro ubiquitin binding assays, mutagenesis, live-cell fluorescence microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — quantitative phosphoproteomics with multiple orthogonal methods (in vitro binding, mutagenesis, imaging); independently replicates and extends PMID:26365381\",\n      \"pmids\": [\"27035970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Structural biology (crystal structure), isothermal titration calorimetry, mutagenesis, in vitro ubiquitin binding assays, co-localization imaging\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation by mutagenesis and in vitro binding assays in single study\",\n      \"pmids\": [\"29394115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"High-resolution live-cell imaging, loss-of-function (E478G mutant expression), co-localization with ubiquitinated mitochondria\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell imaging with functional mutagenesis, replicated across multiple studies\",\n      \"pmids\": [\"25801386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Phase-separated fluorescent foci assays, co-immunoprecipitation, loss-of-function (OPTN-ATG9A interaction mutants), mitophagy induction by mitochondria-targeted ubiquitin chains\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mutant rescue experiments, novel chemical-induced ubiquitination tools, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32556086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic epistasis using selective knockout and rescue experiments, co-immunoprecipitation, live-cell imaging\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple KO lines; largely a commentary/extension of PMID:32556086 with limited additional experimental detail in abstract\",\n      \"pmids\": [\"32892694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression in Neuro2A cells, co-immunoprecipitation, LC3 flux assay, knockdown of autophagy components, IB isolation by sorting\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional readouts, mutagenesis, autophagy flux assays; single lab with multiple methods\",\n      \"pmids\": [\"25484089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, knockdown (shRNA), overexpression, LC3-II immunoblot, cell death assays in RGC-5 cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, shRNA knockdown with specific phenotypic readouts; single lab, multiple methods\",\n      \"pmids\": [\"23357852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown, catalytically inactive mutant expression, co-localization imaging, autophagy flux assays, cell death assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with rescue, catalytic mutants, multiple readouts; single lab\",\n      \"pmids\": [\"24752605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Live-cell imaging, correlative light-electron microscopy (CLEM), TBK1 inhibitor treatment, loss-of-function\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLEM, pharmacological inhibition with functional readouts; single lab\",\n      \"pmids\": [\"30404831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Live-cell imaging, proximity-labeling proteomics (BioID), co-immunoprecipitation, loss-of-function, cytokine measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics with co-IP validation and functional signaling readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32376785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"OPTN-deficient mouse model, viral infection challenge, co-immunoprecipitation (OPTN with VP16 and gB), necroptosis inhibitor rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model, co-IP substrate identification, pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"34518549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"optn-/- mouse model, lentivirus rescue, loss-of-function mutant analysis, MSC transplantation, FABP3 knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with rescue experiments, novel substrate identification; single lab, multiple methods\",\n      \"pmids\": [\"33143524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ectopic expression in BV2 cells and APP/PS1 mice, ELISA, immunofluorescence, siRNA knockdown\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in vivo mouse model, siRNA knockdown with specific signaling readouts; single lab\",\n      \"pmids\": [\"34861878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitinase recruitment assays, K63-ubiquitin chain analysis, dendritic cell knockout, cytokine measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitin chain analysis, KO with functional cytokine readouts; single lab, multiple methods\",\n      \"pmids\": [\"35145029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, protease cleavage site mapping, OPTN knockdown/overexpression, viral replication assays, TBK1/IRF3 phosphorylation measurement\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP substrate identification, cleavage site determination, signaling readouts; single lab\",\n      \"pmids\": [\"37930946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assays, SUMOylation site mutagenesis, OPTN knockdown, ACSL4 degradation assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, MS identification of modification sites, mutagenesis, knockdown with degradation readouts; single lab\",\n      \"pmids\": [\"39875520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry (substrate identification), co-immunoprecipitation, microscale thermophoresis, OPTN knockdown/overexpression, OPTN-/- mouse hepatocyte model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS substrate ID, co-IP, MST binding assay, knockout model; single lab, multiple methods\",\n      \"pmids\": [\"39099169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"OPTN knockdown, RCHY1 knockdown, ubiquitin linkage analysis, TBK1 phosphorylation assays, domain deletion analysis, live-cell imaging\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown, ubiquitin chain analysis, phosphorylation assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38536750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Single and double knockout zebrafish, overexpression rescue experiments, Lc3 colocalization with mycobacteria, infection susceptibility assays\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double knockout epistasis in zebrafish, overexpression rescue with Lc3 functional readout; single lab\",\n      \"pmids\": [\"38264729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-localization imaging, domain mapping by deletion analysis\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid with domain mapping and co-localization; replicated interaction context but limited in vitro validation\",\n      \"pmids\": [\"11137014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence, pharmacological perturbation (nocodazole, brefeldin A), immunohistochemistry during differentiation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with pharmacological perturbations and differentiation-linked translocation; single lab, chicken ortholog\",\n      \"pmids\": [\"12169269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"OPTN knockout MEF cells, lentiviral in vivo motor cortex injection, cytokine ELISA, NF-κB reporter assays, histological cell death analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo lentiviral model with multiple cytokine readouts; single lab\",\n      \"pmids\": [\"30519240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, nuclear localization imaging, TBK1 knockdown, siRNA Atg5 knockdown, ER stress marker immunoblot, autophagy flux assays, cell death assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional rescue by knockdown and pharmacological inhibition; single lab, multiple methods\",\n      \"pmids\": [\"33548116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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%.\",\n      \"method\": \"Multiplexed CRISPR screen, OPTN knockdown/overexpression, mitochondrial respiration assays (Seahorse), ROS measurement, murine transplantation model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen for epistasis, in vivo transplantation model, mitochondrial function assays; multiple orthogonal methods\",\n      \"pmids\": [\"37439113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic human cell model with pharmacological rescue and in vivo validation; single lab\",\n      \"pmids\": [\"39425218\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OPTN (optineurin) functions as a multifunctional selective autophagy receptor that recognizes ubiquitin-decorated cargo (mitochondria, protein aggregates, lysosomes, viral proteins, melanosomes, and other substrates) via its UBAN domain, which preferentially binds linear ubiquitin chains; TBK1 constitutively associates with OPTN and, upon ubiquitin-chain-triggered recruitment to cargo, phosphorylates OPTN at S177 (enhancing LC3/ATG8 binding), S473, and S513 (enhancing ubiquitin-chain binding and mitochondrial retention) in a self-amplifying positive feedback loop; beyond ATG8 binding, OPTN also interacts directly with ATG9A vesicles to nucleate de novo autophagosomal membrane biogenesis at ubiquitinated cargo; OPTN additionally dampens NF-κB and IRF3 signaling by sequestering LUBAC and other positive regulators in an ATG9A-positive perinuclear compartment, and facilitates RIPK1 ubiquitination and degradation via its UBAN-death domain interaction; disease-causing mutations (E50K, E478G, M98K, 2bpIns) variously disrupt ubiquitin binding, dominant-negatively impair autophagosome maturation through MYO6/TOM1 interactions, constitutively activate TBK1, or aberrantly activate NF-κB, linking OPTN dysfunction to glaucoma, ALS, and neurodegeneration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OPTN (optineurin) is a multifunctional selective autophagy receptor that recognizes ubiquitin-decorated cargo and links cargo recognition to autophagosome biogenesis and innate immune signaling [#0, #4]. 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 [#2]. 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 [#0, #1]. 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 [#4, #5]. Through these activities OPTN clears a broad substrate range, including PARKIN-tagged damaged mitochondria during mitophagy [#3], aggregated huntingtin and TDP-43 inclusion bodies via K63-linked ubiquitin [#6], damaged lysosomes [#9], viral proteins targeted during HSV-1 and Seneca Valley virus infection [#11, #15], and metabolic substrates such as FABP3, ACSL4 and GCDH whose turnover depends on K63-linked ubiquitination [#12, #16, #17]. 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-\\u03baB and IRF3 activation [#10], and by binding the RIPK1 death domain through its UBAN domain to promote RIPK1 ubiquitination and degradation [#13]. 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 [#3, #6]; E50K drives autophagic-lysosomal degradation defects with reduced mTORC1 signaling in retinal ganglion cells [#25]; M98K promotes excessive transferrin-receptor autophagy and RAB12-dependent cell death [#7]; and a 2bp-insertion mutant constitutively activates TBK1 and induces ER-stress-dependent cell death [#23], collectively linking OPTN dysfunction to glaucoma, ALS and neurodegeneration.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid and domain-mapping co-localization in mammalian cells\",\n      \"pmids\": [\"11137014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstration of autophagy function\", \"Interaction not validated in vitro with purified proteins\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the basal subcellular localization of OPTN at the Golgi, distinguishing structural from functional dependence using pharmacological disruption.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence and nocodazole/brefeldin A perturbation in chicken ortholog\",\n      \"pmids\": [\"12169269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chicken ortholog; human relevance inferred\", \"Mechanism of Golgi targeting not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"High-resolution live-cell imaging with E478G loss-of-function in HeLa cells\",\n      \"pmids\": [\"25801386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve TBK1 phosphoregulation\", \"Membrane biogenesis mechanism not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Overexpression, co-IP, LC3 flux assays and inclusion-body isolation in Neuro2A cells\",\n      \"pmids\": [\"25484089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Largely overexpression-based\", \"Endogenous flux contribution not quantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Quantitative phosphoproteomics, in vitro ubiquitin binding, mutagenesis and live-cell imaging\",\n      \"pmids\": [\"26365381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of phospho-enhanced binding not resolved here\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Quantitative proteomics, in vitro binding, mutagenesis and fluorescence microscopy\",\n      \"pmids\": [\"27035970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Parkin-independent pathway not fully reconstituted\", \"Chain-type selectivity in cells incompletely mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Crystal structure, ITC, mutagenesis and co-localization imaging\",\n      \"pmids\": [\"29394115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospho-UBAN structure not solved\", \"Selectivity over K63 chains in cells not fully reconciled\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified OPTN–ATG9A interaction as a distinct membrane-biogenesis function beyond ATG8 binding, nucleating autophagosomal membranes at ubiquitinated mitochondria.\",\n      \"evidence\": \"Phase-separation foci assays, reciprocal co-IP, interaction mutants and chemically induced mitochondrial ubiquitination\",\n      \"pmids\": [\"32556086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular geometry of ATG9A engagement unresolved\", \"Lipid-source contribution not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned the OPTN–ATG9A and CALCOCO2–RB1CC1 axes as two independent membrane-initiation routes on damaged mitochondria.\",\n      \"evidence\": \"Genetic epistasis with KO/rescue lines, co-IP and live-cell imaging\",\n      \"pmids\": [\"32892694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited additional experimental detail; largely extends prior work\", \"Cross-talk between axes not quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed OPTN as an immune brake that relocates to ATG9A-positive perinuclear foci to sequester LUBAC, CYLD and TBK1 and dampen NF-\\u03baB/IRF3 signaling, with glaucoma mutations causing aberrant constitutive foci.\",\n      \"evidence\": \"Live-cell imaging, BioID proximity proteomics, co-IP and cytokine assays\",\n      \"pmids\": [\"32376785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether sequestration requires autophagy is unclear\", \"Endogenous foci dynamics not fully characterized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended OPTN/TBK1 function to lysosomal quality control, showing recruitment to alpha-synuclein-fibril-damaged ubiquitylated lysosomes with TBK1-dependent LC3 recruitment.\",\n      \"evidence\": \"Live-cell imaging, CLEM and TBK1 inhibition in microglial cells\",\n      \"pmids\": [\"30404831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct OPTN ubiquitin engagement on lysosomes not biochemically shown\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated OPTN-mediated antiviral autophagy in vivo, targeting HSV-1 VP16 and gB for degradation and protecting against lethal CNS infection and necroptosis.\",\n      \"evidence\": \"OPTN-deficient mouse infection challenge, co-IP and necroptosis inhibitor rescue\",\n      \"pmids\": [\"34518549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin-tagging step on viral proteins not defined\", \"Necroptosis link mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed OPTN restrains RIPK1-driven NF-\\u03baB inflammation via UBAN–death-domain binding promoting RIPK1 degradation, and limits AIM2 inflammasome activation.\",\n      \"evidence\": \"Co-IP, ectopic expression in BV2 cells and APP/PS1 mice, siRNA and ELISA\",\n      \"pmids\": [\"34861878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect RIPK1 ubiquitination control unclear\", \"AIM2 transcriptional mechanism undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked an ALS-associated 2bp-insertion mutant to constitutive TBK1 activation, ER stress and autophagy-dependent motor neuron death via nuclear mislocalization.\",\n      \"evidence\": \"Co-IP, localization imaging, TBK1/Atg5 knockdown and ER-stress inhibitor rescue in NSC-34 cells\",\n      \"pmids\": [\"33548116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear mislocalization unknown\", \"Endogenous mutant context not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected the ALS E478G mutation to aberrant NF-\\u03baB activation and in vivo neuroinflammation and neuronal death, supporting a gain-of-toxic-signaling component.\",\n      \"evidence\": \"Optn-/- MEFs, lentiviral motor-cortex overexpression, NF-\\u03baB reporters and cytokine ELISA\",\n      \"pmids\": [\"30519240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-driven; physiological levels untested\", \"Relationship to autophagy defect not integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established functional redundancy of OPTN with p62 and Dram1 in antibacterial xenophagy, clarifying compensatory receptor logic.\",\n      \"evidence\": \"Single/double knockout and overexpression rescue in Mycobacterium-infected zebrafish\",\n      \"pmids\": [\"38264729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of compensation unresolved\", \"Mammalian generalizability untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened OPTN substrate scope to metabolism by identifying FABP3 as a selective autophagy substrate whose accumulation drives bone loss in Optn-deficient mice.\",\n      \"evidence\": \"optn-/- mouse model with lentivirus rescue, MSC transplantation and FABP3 knockdown\",\n      \"pmids\": [\"33143524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FABP3 ubiquitin tag and receptor interface not mapped\", \"Tissue specificity of substrate selection unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified OPTN as the sole non-redundant mitophagy receptor sustaining AML proliferation, revealing a context-dependent pro-survival role.\",\n      \"evidence\": \"Multiplexed CRISPR screen, respiration/ROS assays and murine transplantation model\",\n      \"pmids\": [\"37439113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why redundancy is lost in AML is unexplained\", \"Druggable dependency mechanism undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, cleavage-site mapping, knockdown/overexpression and TBK1/IRF3 phosphorylation assays\",\n      \"pmids\": [\"37930946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Fragment fates in cells not fully characterized\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended OPTN substrate range to GCDH and showed VCP stabilizes BECN1 to boost OPTN-mediated mitophagy initiation, protecting against drug-induced liver injury.\",\n      \"evidence\": \"MS substrate ID, co-IP, microscale thermophoresis and OPTN-/- hepatocyte model\",\n      \"pmids\": [\"39099169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"VCP–OPTN interface not structurally defined\", \"Selectivity for GCDH unexplained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, MS modification-site mapping, mutagenesis and degradation assays\",\n      \"pmids\": [\"39875520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct OPTN–ACSL4 binding interface not defined\", \"Physiological setting of regulation limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Knockdown, ubiquitin-linkage analysis, phosphorylation assays and live-cell imaging\",\n      \"pmids\": [\"38536750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"S187 phosphosite role versus canonical sites unclear\", \"In vivo melanophagy relevance untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Isogenic hPSC-derived RGC CRISPR knock-in, flux assays, mTORC1 immunoblot and pharmacological rescue with in vivo validation\",\n      \"pmids\": [\"39425218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How E50K alters mTORC1/AMPK is mechanistically incomplete\", \"Single isogenic system\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 3, 17]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4, 10, 20]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 3, 4, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 11, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3, 17, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TBK1\", \"ATG9A\", \"RIPK1\", \"MYO6\", \"TOM1\", \"RAB8\", \"RAB12\", \"VCP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}