Optineurin

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Optineurin

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Optineurin

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Optineurin</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[optn](/genes/optn)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q96CV9](https://www.uniprot.org/uniprot/Q96CV9)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~67 kDa</td>
</tr>
<tr>
<td class="label">Amino Acids</td>
<td>577</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cytoplasm, Golgi apparatus, autophagosomes, mitochondrial contact sites</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Selective autophagy receptors (SQSTM1-like)</td>
</tr>
<tr>
<td class="label">Modification</td>
<td>Site</td>
</tr>
<tr>
<td class="label">Phosphorylation</td>
<td>Ser177</td>
</tr>
<tr>
<td class="label">Phosphorylation</td>
<td>Ser473</td>
</tr>
<tr>
<td class="label">Phosphorylation</td>
<td>Ser513</td>
</tr>
<tr>
<td class="label">Ubiquitination</td>
<td>Multiple Lys</td>
</tr>
<tr>
<td class="label">Deubiquitination</td>
<td>Multiple Lys</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer-disease" style="color:#ef9a9a">ALZHEIMER DISEASE</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href

...

Optineurin

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Optineurin</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[optn](/genes/optn)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q96CV9](https://www.uniprot.org/uniprot/Q96CV9)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~67 kDa</td>
</tr>
<tr>
<td class="label">Amino Acids</td>
<td>577</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cytoplasm, Golgi apparatus, autophagosomes, mitochondrial contact sites</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Selective autophagy receptors (SQSTM1-like)</td>
</tr>
<tr>
<td class="label">Modification</td>
<td>Site</td>
</tr>
<tr>
<td class="label">Phosphorylation</td>
<td>Ser177</td>
</tr>
<tr>
<td class="label">Phosphorylation</td>
<td>Ser473</td>
</tr>
<tr>
<td class="label">Phosphorylation</td>
<td>Ser513</td>
</tr>
<tr>
<td class="label">Ubiquitination</td>
<td>Multiple Lys</td>
</tr>
<tr>
<td class="label">Deubiquitination</td>
<td>Multiple Lys</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer-disease" style="color:#ef9a9a">ALZHEIMER DISEASE</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">717 edges</a></td>
</tr>
</table>

Optineurin is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Pathway Diagram

Mermaid diagram (expand to render)

Overview

[optineurin](/proteins/optineurin) (OPTN, optic neuropathy-inducing protein) is a multifunctional adaptor protein that plays essential roles in selective [autophagy](/mechanisms/autophagy-lysosome-neurodegeneration), vesicular trafficking, [nf-kb](/entities/nf-kb) signaling regulation, and innate immune signaling. Encoded by the [optn](/genes/optn) gene on chromosome 10p13, optineurin functions as a selective [autophagy](/entities/autophagy) receptor for damaged [mitochondrial-dynamics](/entities/mitochondrial-dynamics), intracellular bacteria, and protein aggregates, working in close partnership with [TBK1[/proteins/[TBK1](/proteins/TBK1) kinase.[@wild2011] Mutations in OPTN cause both familial [als](/diseases/amyotrophic-lateral-sclerosis) and primary open-angle glaucoma (POAG), establishing optineurin as a critical link between neurodegeneration and selective autophagy dysfunction.[@maruyama2010] The convergence of OPTN and [TBK1[/proteins/[TBK1](/proteins/TBK1) mutations in ALS has illuminated the central importance of autophagy receptor-kinase signaling in [motor-neurons](/cell-types/motor-neurons) survival. [@maruyama2010]

--- [@ying2016]

Structure and Domains

Optineurin is a 577-amino acid, ~67 kDa cytoplasmic protein with multiple protein-protein interaction domains:[@ying2016] [@richter2016]

Key Functional Domains

Coiled-coil domains (CC1, CC2): Mediate self-dimerization and interactions with myosin VI, Rab8, and [huntingtin](/proteins/huntingtin). The CC1 domain (residues 78–185) contains the [TBK1[/proteins/[TBK1](/proteins/TBK1)-binding region essential for kinase recruitment. CC1 also mediates optineurin homo-oligomerization, which is important for forming multivalent autophagy receptor complexes
LIR (LC3-interacting region) motif (residue 178): Contains the FEVI motif that binds LC3/GABARAP on autophagosomal membranes. TBK1-mediated phosphorylation at Ser177 dramatically enhances LIR-LC3 binding affinity, increasing it by ~20-fold[@richter2016]
UBAN (ubiquitin-binding in ABIN and NEMO) domain (residues 412–520): Binds linear (M1-linked) and K63-linked polyubiquitin chains with high specificity. The UBAN domain forms a parallel coiled-coil dimer that creates a symmetric ubiquitin-binding interface. Critical for both [nf-kb](/entities/nf-kb) signaling regulation and cargo recognition in selective autophagy[@li2018]
Zinc finger domain (C-terminal): Involved in protein-protein interactions and cargo recognition. Contains a C2H2-type zinc finger motif that contributes to ubiquitin binding cooperativity
NEMO-like domain: Shares structural homology with NEMO ([nf-kb](/entities/nf-kb) essential modulator), reflecting optineurin's evolutionary relationship and role in [nf-kb](/entities/nf-kb) signaling

Post-Translational Modifications

Optineurin function is extensively regulated by post-translational modifications: [@nakazawa2016]

Normal Function

Selective Autophagy Receptor

Optineurin functions as a selective autophagy receptor for multiple cargo types:[@lazarou2015]

[mitophagy](/mechanisms/mitophagy): Optineurin is recruited to damaged mitochondria following [pink1-protein](/proteins/pink1-protein)/[parkin](/proteins/parkin)-mediated ubiquitination of outer mitochondrial membrane proteins. The UBAN domain recognizes ubiquitin chains on mitochondria, while the LIR motif recruits autophagosomes. [TBK1[/proteins/[TBK1](/proteins/TBK1) phosphorylation amplifies this process, creating a feed-forward signaling cascade that ensures efficient engulfment of damaged mitochondria. Optineurin is considered the dominant autophagy receptor for Parkin-dependent mitophagy in several cell types, more important than [p62-sqstm1](/proteins/p62-sqstm1) or NDP52 in this context.

Xenophagy: Optineurin is a primary receptor for antibacterial autophagy, targeting ubiquitinated intracellular bacteria (Salmonella, Mycobacterium) for autophagic destruction. TBK1-mediated phosphorylation at Ser177 is required for efficient xenophagy.

Aggrephagy: Optineurin participates in clearance of ubiquitinated protein aggregates, complementing [p62-sqstm1](/proteins/p62-sqstm1) and NBR1 in the autophagic degradation of misfolded proteins. This is particularly relevant in [motor-neurons](/cell-types/motor-neurons) where [tdp-43](/proteins/tdp-43) and [sod1-protein](/proteins/sod1-protein) aggregates accumulate in ALS.

TBK1 Signaling Axis: The Mitophagy Contact Site

The optineurin-TBK1 interaction is central to selective autophagy. A 2024 study in The EMBO Journal revealed that optineurin provides a physical mitophagy contact site for TBK1 activation:[@yamano2024]

Optineurin is recruited to ubiquitinated damaged mitochondria via its UBAN domain

Optineurin simultaneously contacts pre-autophagosomal structures (PAS) via its LIR motif

At this contact site between damaged mitochondria and autophagosome formation sites, TBK1 is activated via hetero-autophosphorylation

Activated TBK1 phosphorylates optineurin at Ser177 and Ser473, dramatically enhancing both LC3 binding and ubiquitin binding

This creates a positive feedback loop: more optineurin recruitment → more TBK1 activation → stronger optineurin-cargo binding → accelerated autophagosome formation

TBK1 also phosphorylates other autophagy receptors ([p62-sqstm1](/proteins/p62-sqstm1), NDP52), amplifying the autophagic response

This contact site model explains why both OPTN and TBK1 mutations cause ALS: disruption at either end of the optineurin-TBK1 axis impairs the mitophagy contact site and prevents efficient clearance of damaged mitochondria.

Phase Separation and Condensate Formation

Optineurin participates in [liquid-liquid-phase-separation](/mechanisms/liquid-liquid-phase-separation) (LLPS), forming dynamic biomolecular condensates that are critical for autophagy function. A 2024 study demonstrated that autophagy adaptors including optineurin form sheet-like liquid condensates on damaged mitochondria during Parkin-dependent mitophagy:[@yamano2024a]

Optineurin-ubiquitin condensates are dynamic and liquid-like, undergoing fusion and fission
The fluidity of these condensates is essential for mitophagy activity — reducing condensate fluidity suppresses ATG9 vesicle recruitment and impairs mitophagy
ALS-associated mutations (E478G) in the UBAN domain disrupt condensate formation and dynamics
TBK1 phosphorylation modulates condensate properties, potentially by altering multivalent interactions between optineurin, ubiquitin, and LC3

This connects optineurin dysfunction to the broader theme of pathological phase transitions in neurodegenerative diseases, where proteins like [tdp-43](/proteins/tdp-43) and [fus-protein](/proteins/fus-protein) undergo aberrant phase separation and aggregation.

NF-kB Signaling Regulation

Optineurin negatively regulates [nf-kb](/entities/nf-kb) signaling by competing with NEMO for ubiquitin chain binding. Through its UBAN domain, optineurin sequesters linear ubiquitin chains, preventing NEMO-mediated [nf-kb](/entities/nf-kb) activation. Loss of optineurin function leads to enhanced [nf-kb](/entities/nf-kb)-driven [neuroinflammation](/mechanisms/neuroinflammation), chronic inflammatory signaling, and increased production of pro-inflammatory cytokines including TNF-alpha, IL-1beta, and IL-6.

Vesicular Trafficking

Optineurin interacts with Rab8, myosin VI, and [huntingtin](/proteins/huntingtin) to regulate:

Golgi maintenance and post-Golgi trafficking
Secretory vesicle transport
Receptor recycling and endosomal trafficking
Exocytosis and membrane protein delivery

Innate Immune Signaling

Beyond NF-kB, optineurin plays roles in type I interferon signaling through the cGAS-[STING pathway](/entities/sting-pathway). Optineurin promotes [sting-pathway](/mechanisms/cgas-sting-neurodegeneration)-mediated IRF3 activation via TBK1, contributing to antiviral defense and sterile inflammatory responses. Disruption of this function by ALS-causing mutations may contribute to dysregulated interferon signaling in Motor [neurons](/entities/neurons) Disease.[@bakshi2025]

Role in Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis (ALS)

OPTN mutations account for approximately 1–4% of familial [als](/diseases/amyotrophic-lateral-sclerosis) cases and some sporadic cases:[@maruyama2010]

Key ALS mutations:

E478G: Located in the UBAN domain, abolishes ubiquitin binding. Causes aggressive ALS with [tdp-43](/proteins/tdp-43)-positive inclusions. Disrupts condensate formation on damaged mitochondria
Q398X: Truncation mutation removing the UBAN domain and zinc finger. Causes severe ALS
E696K: Zinc finger mutation with reduced autophagy function
R96L: Impairs optineurin self-dimerization and TBK1 interaction
Homozygous deletions: Complete OPTN loss causes ALS, demonstrating that loss-of-function is sufficient for disease

Pathogenic mechanisms:

Impaired [mitophagy](/mechanisms/mitophagy) leading to accumulation of damaged mitochondria and [oxidative-stress](/mechanisms/oxidative-stress)
Defective clearance of [tdp-43](/proteins/tdp-43) and [sod1-protein](/proteins/sod1-protein) aggregates via aggrephagy
Enhanced [neuroinflammation](/mechanisms/neuroinflammation) through derepressed NF-kB signaling
Disrupted vesicular trafficking and Golgi fragmentation in [motor-neurons](/cell-types/motor-neurons)
Impaired phase separation dynamics at mitophagy contact sites

The convergence of OPTN, [TBK1[/proteins/[TBK1](/proteins/TBK1), [p62-sqstm1](/proteins/p62-sqstm1), and [vcp](/genes/vcp) mutations in ALS establishes autophagy dysfunction as a central disease mechanism, defining a "selective autophagy" subtype of ALS.

Glaucoma

OPTN mutations were first identified as a cause of normal-tension glaucoma (NTG), a neurodegenerative disease of retinal ganglion cells (RGCs):[@rezaie2002]

E50K mutation: The most studied glaucoma-associated variant, causing enhanced TBK1 interaction and aberrant autophagosome formation. E50K OPTN induces RGC death through excessive autophagy activation and ER stress[@minegishi2013]
M98K mutation: Risk factor for NTG, activating TBK1-dependent autophagy and retinal cell death
Shared ALS-glaucoma mechanisms: Both conditions involve autophagy dysregulation, mitochondrial dysfunction, and selective neuronal death, suggesting a shared neurodegenerative mechanism linking long-projecting [neurons](/entities/neurons) (motor [neurons](/entities/neurons) and retinal ganglion cells)

Connections to Other Neurodegenerative Diseases

[huntington-pathway](/mechanisms/huntington-pathway): Optineurin interacts directly with [huntingtin](/proteins/huntingtin) protein; mutant [huntingtin](/proteins/huntingtin) disrupts optineurin-mediated vesicular trafficking and Golgi maintenance
[alzheimers](/diseases/alzheimers-disease): Optineurin is found in neurofibrillary tangles and dystrophic neurites in AD brain, suggesting involvement in tau]/proteins/tau] pathology. Optineurin-mediated mitophagy may be impaired in AD [neurons](/entities/neurons)
[parkinsons](/diseases/parkinsons-disease): OPTN participates in [pink1-protein](/proteins/pink1-protein)/[parkin](/proteins/parkin)-dependent [mitophagy](/mechanisms/mitophagy), and OPTN deficiency may contribute to [dopaminergic-neurons](/dopaminergic-neurons) vulnerability in PD
[Paget's disease of bone: OPTN mutations (D474N) are associated with Paget's disease, linking optineurin to osteoclast NF-kB signaling
Crohn's disease: Rare OPTN variants are associated with inflammatory bowel disease, consistent with its role in xenophagy and immune regulation

Animal Models

OPTN Knockout Mice

OPTN-null mice develop late-onset motor axon degeneration, gliosis, and neurofilament abnormalities, but with slower progression than human ALS[@ito2016]
Conditional deletion of OPTN in [neurons](/entities/neurons) causes accumulation of damaged mitochondria, increased [oxidative-stress](/mechanisms/oxidative-stress), and progressive motor dysfunction
OPTN knockout mice crossed with SOD1-G93A mice show accelerated disease progression, demonstrating genetic interaction

E50K Knock-in Mice

E50K OPTN knock-in mice develop progressive retinal ganglion cell loss resembling normal-tension glaucoma
Enhanced TBK1 activation and autophagosome accumulation are observed in RGCs
These mice have been used to test TBK1 inhibitors and autophagy modulators as potential glaucoma therapies

OPTN-TDP-43 Interaction Models

Loss of OPTN in mice leads to accumulation of [tdp-43](/proteins/tdp-43)-positive cytoplasmic inclusions in spinal motor [neurons](/entities/neurons)
This demonstrates that OPTN-dependent autophagy is required for [tdp-43](/proteins/tdp-43) clearance, connecting the two most common pathological hallmarks of ALS

Therapeutic Targeting

TBK1 activators: Small molecules enhancing TBK1-OPTN signaling to boost selective autophagy and mitophagy. AZVS-1811 is a TBK1 activator in preclinical development
Gene therapy: AAV-mediated OPTN overexpression in preclinical glaucoma and ALS models has shown neuroprotective effects in retinal ganglion cells and motor [neurons](/entities/neurons)
[autophagy](/mechanisms/autophagy-lysosome-neurodegeneration) modulators: Compounds enhancing OPTN-dependent mitophagy for neuroprotection, including rapamycin analogs and [tfeb](/proteins/tfeb) activators
Anti-inflammatory strategies: Targeting OPTN-NF-kB axis to reduce neuroinflammation while preserving autophagy function
Condensate modulators: Emerging approaches to restore normal phase separation dynamics at mitophagy contact sites
[sting-pathway](/mechanisms/cgas-sting-neurodegeneration) pathway modulation: Targeting the OPTN–TBK1–[sting-pathway](/mechanisms/cgas-sting-neurodegeneration) axis to reduce [neuroinflammation](/mechanisms/neuroinflammation) while maintaining autophagy

External Links

[UniProt — OPTN (Q96CV9)](https://www.uniprot.org/uniprot/Q96CV9)
[NCBI Gene — OPTN](https://www.ncbi.nlm.nih.gov/gene/10133)
[OMIM — OPTN (602432)](https://omim.org/entry/602432)
[PDB — OPTN UBAN domain (5B83)](https://www.rcsb.org/structure/5B83)
[Allen Brain Atlas — OPTN](https://human.brain-map.org/microarray/search/show?search_term=OPTN)

Brain Atlas Resources

Allen Human Brain Atlas: [Optineurin expression search](https://human.brain-map.org/microarray/search/show?search_term=Optineurin)
Allen Mouse Brain Atlas: [Optineurin search](https://mouse.brain-map.org/search/index.html?query=Optineurin)
Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
BrainSpan Developmental Transcriptome: [Optineurin developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=Optineurin)

Background

The study of Optineurin has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

[Wild et al., Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth, Science (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21617041/)

[Maruyama et al., Mutations of optineurin in amyotrophic lateral sclerosis, Nature (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20428114/)

[Unknown, Ying & Bhatt, Optineurin — multifunctional roles in diseases and gene therapy, Trends in Molecular Medicine (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27693724/)

[Richter et al., Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains, PNAS (2016) (2016)](https://doi.org/10.1073/pnas.1523926113)

[Li et al., Structural insights into the ubiquitin recognition by OPTN and its regulation by TBK1, Autophagy (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29130380/)

[Lazarou et al., The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy, Nature (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25417166/)

[Yamano et al., Optineurin provides a mitophagy contact site for TBK1 activation, The EMBO Journal (2024) (2024)](https://doi.org/10.1038/s44318-024-00036-1)

[Yamano et al., Autophagy adaptors mediate Parkin-dependent mitophagy by forming sheet-like liquid condensates, The EMBO Journal (2024) (2024)](https://doi.org/10.1038/s44318-024-00272-5)

[Bakshi et al., Structural and functional perspectives of optineurin in autophagy, immune signaling, and cancer, Cells (2025) (2025)](https://doi.org/10.3390/cells14221746)

[Rezaie et al., Adult-onset primary open-angle glaucoma caused by mutations in optineurin, Science (2002) (2002)](https://pubmed.ncbi.nlm.nih.gov/11834836/)

[Minegishi et al., Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates POAG, Human Molecular Genetics (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/23918786/)

[Ito et al., RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS, Science (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27576665/)

[Nakazawa et al., Linear ubiquitination is involved in the pathogenesis of optineurin-associated ALS, Nature Communications (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27035970/)

[Li et al., Structural insights into the interaction of optineurin and TBK1, Nature Communications (2016) (2016)](https://doi.org/10.1038/ncomms12708)

Pathway Diagram

The following diagram shows the key molecular relationships involving Optineurin discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

OPTINEURIN

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slug	proteins-optineurin
kg_node_id	OPTINEURIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-6927e20e26b2
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-optineurin'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

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Certainty

55%

Debates

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Outgoing

27

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📗 Cite This Artifact

Optineurin

Optineurin

Introduction

Optineurin

Introduction

Pathway Diagram

Overview

Structure and Domains

Key Functional Domains

Post-Translational Modifications

Normal Function

Selective Autophagy Receptor

TBK1 Signaling Axis: The Mitophagy Contact Site

Phase Separation and Condensate Formation

NF-kB Signaling Regulation

Vesicular Trafficking

Innate Immune Signaling

Role in Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis (ALS)

Glaucoma

Connections to Other Neurodegenerative Diseases

Animal Models

OPTN Knockout Mice

E50K Knock-in Mice

OPTN-TDP-43 Interaction Models

Therapeutic Targeting

See Also

External Links

Brain Atlas Resources

Background

References

Pathway Diagram

💬 Discussion