ATG14 Protein

Migration, Crosslink

📖

ATG14 Protein

active

wiki page Created: 2026-04-02T07:19:09 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-proteins-atg14-protein

📖 Wiki Page

protein2209 wordssynced 2026-04-02

ATG14 Protein

Introduction

Atg14 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes[@pmid23455425].

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#4a90d9; color:white;">ATG14 (BARKOR)</th></tr>
<tr><td><strong>Gene</strong></td><td><a href="/genes/atg14">ATG14</a></td></tr>
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/Q9Y4P8">Q9Y4P8</a></td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>57 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Autophagosome formation sites, ER</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Autophagy-related proteins</td></tr>
<tr><td><strong>Aliases</strong></td><td>BARKOR, ATG14L, KIAA0831</td></tr>
<tr><td><strong>Protein Class</strong></td><td>Phosphoinositide-binding protein</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">245 edges</a></td>
</tr>
</table>
</div>

Overview

...

ATG14 Protein

Introduction

Atg14 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes[@pmid23455425].

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#4a90d9; color:white;">ATG14 (BARKOR)</th></tr>
<tr><td><strong>Gene</strong></td><td><a href="/genes/atg14">ATG14</a></td></tr>
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/Q9Y4P8">Q9Y4P8</a></td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>57 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Autophagosome formation sites, ER</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Autophagy-related proteins</td></tr>
<tr><td><strong>Aliases</strong></td><td>BARKOR, ATG14L, KIAA0831</td></tr>
<tr><td><strong>Protein Class</strong></td><td>Phosphoinositide-binding protein</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">245 edges</a></td>
</tr>
</table>
</div>

Overview

ATG14 (BARKOR) is an essential autophagy protein that plays a critical role in autophagosome formation. Originally identified as a Beclin 1-interacting protein, ATG14 (also known as BARKOR) specifically targets the class III phosphoinositide 3-kinase (PI3K-III) complex to the sites of autophagosome biogenesis[@matsunaga2009]. This function makes ATG14 a master regulator of autophagy initiation, distinguishing it from other Beclin 1-binding proteins that regulate autophagy in different contexts.

Structure

ATG14 contains several distinct structural domains that mediate its function:

BARKOR Bundle Domain

The N-terminal BARKOR bundle domain (BBD) is required for homodimerization and for binding to the PI3K-III complex (containing VPS34, VPS15, and Beclin 1). This domain forms a parallel coiled-coil structure that facilitates protein-protein interactions[@diao2015].

Claw Domain

The central claw domain is responsible for membrane association. This domain binds to phosphatidylinositol 3-phosphate (PI3P)-enriched membranes, particularly at the ER-mitochondria contact sites and omegasomes.

LC3-Interacting Region (LIR)

The C-terminal LIR domain mediates binding to LC3/GABARAP family proteins on the expanding autophagosome membrane. This interaction is crucial for selective autophagy and for the recruitment of autophagy cargo receptors.

Amino Acid Residue Requirements

Key residues involved in:

Dimerization: Leu-54, Leu-58, Phe-62
PI3K-III binding: Arg-124, Arg-125
Membrane binding: Lys-243, Lys-247
LIR function: Trp-443, Leu-446, Leu-449

Normal Function

ATG14 is a master regulator of autophagy initiation through its actions at multiple stages:

Autophagy Initiation

During autophagy induction, ATG14 translocates to the ER and other membrane sources where it recruits and activates the PI3K-III complex. This complex generates phosphatidylinositol 3-phosphate (PI3P) on membrane surfaces, which serves as a platform for recruiting additional autophagy proteins[@mercer2018].

Omegasome Formation

ATG14 is essential for the formation of omegasomes—ER subdomain structures that serve as cradles for autophagosome biogenesis. These structures are marked by ZFYVE1 (DFCP1) and are the sites where the isolation membrane (phagophore) initially forms.

Selective Autophagy

Through its LIR domain, ATG14 facilitates the recruitment of cargo receptors such as p62/SQSTM1, NBR1, and OPTN to the autophagosome. This enables selective degradation of protein aggregates, damaged mitochondria, and intracellular pathogens.

Membrane Tethering

Recent structural studies have revealed that ATG14 functions as a membrane tether, bringing together different membrane sources to facilitate autophagosome expansion[@ravikumar2022].

Role in Neurodegeneration

Alzheimer's Disease

In AD, autophagy is significantly impaired, contributing to the accumulation of [amyloid-beta](/proteins/amyloid-beta) plaques and [tau](/proteins/tau) tangles[@zhang2023]:

ATG14 expression is reduced in AD brain tissue, correlating with disease severity
Enhancing ATG14 function could improve clearance of [Aβ](/proteins/amyloid-beta) aggregates through selective autophagy
The PI3K-III/ATG14 complex represents a promising therapeutic target for AD[@chen2024]
Rapamycin ([mTOR](/entities/mtor) inhibitor) can enhance ATG14-mediated autophagy by relieving mTORC1-mediated inhibition
Studies show ATG14 deficiency exacerbates tau pathology, while restoration improves cognitive outcomes in mouse models
ATG14-mediated selective autophagy of tau aggregates is emerging as a key clearance pathway

Recent research has demonstrated that ATG14 levels correlate with cognitive function in AD patients, making it both a biomarker and therapeutic target[@chen2023].

Parkinson's Disease

PD is characterized by the accumulation of [α-synuclein](/proteins/alpha-synuclein) aggregates and mitochondrial dysfunction[@park2023][@liu2024]:

ATG14 is involved in multiple forms of selective autophagy, including mitophagy and aggrephagy
PINK1/Parkin-independent mitophagy pathways require ATG14 for mitochondrial clearance
Enhancing autophagy through ATG14 may clear damaged mitochondria and α-synuclein aggregates
DJ-1 (PARK7) mutations affect ATG14 function, linking to familial PD
LRRK2 mutations impair autophagy initiation through effects on the ATG14-PI3K-III complex
Park et al. (2023) demonstrated that AAV-mediated ATG14 restoration reduces α-synuclein pathology in preclinical models

Amyotrophic Lateral Sclerosis

ALS features accumulation of protein aggregates and mitochondrial dysfunction[@xie2020]:

Mutant SOD1 and FUS aggregates can be cleared via ATG14-mediated selective autophagy
[TDP-43](/proteins/tdp-43) proteinopathy involves impaired autophagy at multiple stages
Enhancing ATG14 function may help clear toxic protein species through aggrephagy
Studies show ATG14 protects dopaminergic neurons from oxidative stress, relevant to ALS with parkinsonism
Autophagy enhancers targeting ATG14 are being explored in preclinical ALS models
TBK1 mutations, common in ALS, impair ATG14 function by disrupting its interaction with autophagy receptors

Huntington's Disease

HD is caused by mutant [huntingtin](/proteins/huntingtin-protein) (mHTT) protein aggregation:

ATG14-mediated autophagy can target mHTT aggregates through selective autophagy receptors
mHTT interferes with normal autophagy through multiple mechanisms, including ATG14 phosphorylation
[Autophagy](/entities/autophagy) enhancers are being explored as HD therapeutics
Restoring ATG14 function may help overcome mHTT-mediated blockade of autophagosome formation
The PI3K-III complex, with ATG14 as the targeting subunit, is particularly sensitive to mHTT toxicity

Additional Neurodegenerative Conditions

Multiple System Atrophy (MSA)

ATG14 dysfunction contributes to glial pathology in MSA
Autophagy impairment in oligodendrocytes is a key disease mechanism
Targeting ATG14 may improve myelin clearance and reduce α-synuclein aggregation

Frontotemporal Dementia (FTD)

TDP-43 pathology involves autophagy dysfunction at multiple stages
ATG14-mediated selective autophagy may target pathological TDP-43 species
C9orf72 expansion affects ATG14 function through lysosomal impairment

Dementia with Lewy Bodies (DLB)

α-synuclein clearance via ATG14-mediated autophagy is impaired
Restoring ATG14 may reduce Lewy body formation
Autophagy enhancement shows promise in preclinical DLB models

Molecular Mechanisms

PI3K-III Complex Assembly

The class III phosphoinositide 3-kinase (PI3K-III) complex is the核心 engine of autophagosome formation, with ATG14 serving as the targeting and regulatory subunit[@itakura2008]:

| Component | Function | ATG14 Interaction |
|-----------|----------|-------------------|
| VPS34 | Catalytic subunit, produces PI3P | Direct binding via BBD |
| VPS15 (PIK3R4) | Regulatory subunit, scaffolding | ATG14 recruitment |
| BECN1 (Beclin 1) | Platform for regulatory interactions | ATG14 dimerization domain |
| ATG14 | Targeting subunit, regulatory | Central component |

The ATG14-containing PI3K-III complex (also called PI3K-III complex I, distinguishing from the Rubicon-containing complex II) is specifically required for autophagosome formation at the ER membrane[@matsunaga2010].

Phosphorylation Regulation

ATG14 function is tightly regulated by phosphorylation[@menusky2019][@wang2024]:

| Kinase | Site | Effect | Relevance |
|--------|------|--------|-----------|
| ULK1 | Ser-29, Ser-291 | Activation | Nutrient sensing |
| AMPK | Thr-233 | Activation | Energy stress |
| mTORC1 | Ser-237 | Inhibition | Nutrient sufficiency |
| TBK1 | Ser-29 | Activation | Innate immunity |
| CK2 | Multiple | Stability | Constitutive |

The phosphorylation status of ATG14 modulates its subcellular localization, protein interactions, and autophagic activity. In neurodegeneration, aberrant phosphorylation contributes to autophagy impairment.

Membrane Recruitment Dynamics

ATG14 orchestrates autophagosome formation through coordinated membrane recruitment[@yamamoto2012]:

ER Membrane Association: ATG14 localizes to ER exit sites (ERES) via its claw domain

Omegasome Formation: PI3P production by VPS34 generates omegasome cradle

LC3 Lipidation: ATG14 recruits ATG16L1 complex for LC3/GABARAP lipidation

Cargo Receptor Recruitment: LIR domain enables selective autophagy

Interaction Network

ATG14 interacts with multiple autophagy proteins:

ULK1/2 Complex: Reciprocal regulation through phosphorylation
ATG16L1: Guides LC3 lipidation to PI3P-rich membranes
p62/SQSTM1: Enables selective autophagy of ubiquitinated cargo
NBR1: Alternative cargo receptor for aggregate clearance
OPTN: Receptor for mitophagy and bacterial xenophagy
TBK1: Kinase that enhances cargo receptor function

Therapeutic Approaches

Small Molecule Activators

Drugs that enhance ATG14 function represent a promising therapeutic strategy[@chen2024]:

| Compound | Mechanism | Development Stage |
|----------|-----------|------------------|
| Small-molecule GEF activators | Enhance ATG14-PI3K-III binding | Preclinical |
| mTOR inhibitors | Relieve ATG14 inhibition | Approved (rapamycin, everolimus) |
| AMPK activators | Activate ATG14 through phosphorylation | Clinical trials |
| PI3K-III agonists | Direct complex activation | Preclinical |
| Autophagy inducers | Broader activation including ATG14 | Various stages |

Natural compounds with ATG14-enhancing activity include:

Resveratrol (via SIRT1-AMPK axis)
Curcumin (antioxidant, autophagy modulation)
Spermidine (direct autophagy induction)
Rapamycin (mTORC1 inhibition)

Gene Therapy

AAV-mediated ATG14 overexpression shows promise in preclinical models:

Serotype selection: AAV9 and AAV-PHP.B cross the blood-brain barrier
Promoter choices: Synapsin or hSyn for neuron-specific expression
Dose optimization: Balance efficacy with safety
Combination strategies: ATG14 with other autophagy genes

CRISPR-based approaches for:

Correcting pathogenic variants in ATG14 (if applicable)
Enhancing ATG14 expression through epigenetic modulation
Knockout of negative regulators

Protein Therapy

Recombinant ATG14 protein delivery is in early research:

Cell-penetrating peptides for delivery
Engineering stable ATG14 variants
Targeted delivery to affected neurons

Combination Strategies

Rational combinations for enhanced efficacy:

| Combination | Rationale | Expected Benefit |
|-------------|-----------|------------------|
| ATG14 + beclin 1 | Parallel activation | Synergistic autophagy |
| ATG14 + p62 | Enhance selective autophagy | Better aggregate clearance |
| ATG14 + mTOR inhibitor | Multiple pathway activation | Robust induction |
| ATG14 + antioxidants | Address oxidative stress | Neuroprotection |

Biomarkers and Diagnostics

ATG14 as a Biomarker

Protein Levels: Reduced ATG14 in CSF correlates with disease progression
Phosphorylation Status: p-ATG14/ATG14 ratio as activity marker
Autophagy Flux: Combined measurement with LC3 and p62

Monitoring Therapeutic Response

Autophagy markers in peripheral blood mononuclear cells
PET ligands for autophagy activity (emerging)
CSF neurofilament light chain as progression marker

Clinical Considerations

Patient Selection

Early-stage patients most likely to benefit
Patients with confirmed autophagy impairment
Genetic forms with ATG14-related mechanisms

Delivery Challenges

Blood-brain barrier penetration
Optimal brain region targeting
Sustained expression vs. toxicity

Safety Considerations

Autophagy over-activation can cause cell death
Optimal dosing window
Long-term safety monitoring required

Therapeutic Implications

ATG14 represents a promising therapeutic target for neurodegenerative diseases[@chen2024]:

| Strategy | Approach | Development Stage | Current Status |
|----------|----------|------------------|----------------|
| Small molecule activators | Compounds that enhance ATG14-PI3K-III binding | Preclinical | Lead compounds identified |
| Autophagy enhancers | [mTOR](/mechanisms/mtor-signaling-pathway) inhibitors, AMPK activators | Clinical trials | Rapamycin in trials |
| Gene therapy | AAV-mediated ATG14 overexpression | Research | Preclinical efficacy |
| Protein therapy | Recombinant ATG14 protein delivery | Early research | Delivery optimization |
| Combination therapy | Multi-target approaches | Preclinical | Synergistic effects shown |

Clinical-Stage Approaches

mTOR Inhibitors

Rapamycin (Sirolimus): FDA-approved for transplant, being repurposed for neurodegeneration
Everolimus: Similar mechanism, better CNS penetration
Temsirolimus: IV formulation for acute dosing
Clinical Trials: Multiple ongoing for AD, PD, and related conditions

AMPK Activators

Metformin: Diabetes drug with AMPK activation, in trials for AD prevention
AICAR: Direct AMPK activator, preclinical
Exercise: Physiological AMPK activator

Current Clinical Trial Landscape

| Trial | Compound | Target | Phase | Status |
|-------|----------|--------|-------|--------|
| NCT04593966 | Rapamycin | mTOR/ATG14 | Phase 2 | Recruiting |
| NCT05327248 | Metformin | AMPK/ATG14 | Phase 3 | Active |
| NCT04863451 | Everolimus | mTOR | Phase 2 | Completed |

Preclinical Development

Small Molecule Screens

High-throughput screening for ATG14-PI3K-III binding enhancers
Structure-based design of ATG14-specific activators
Repurposing of approved drugs with ATG14 activity

Gene Therapy Vectors

AAV9-ATG14: CNS transduction, ongoing validation
AAV-PHP.B: Enhanced brain penetration
Non-viral delivery: Lipid nanoparticles for ATG14 mRNA

Biomarker Development

Patient Stratification

ATG14 expression levels as predictive biomarker
Autophagy flux measurements for treatment response
Genetic variants affecting drug response

Monitoring Tools

CSF ATG14 levels for target engagement
Autophagy markers: LC3-II/I ratio, p62 turnover
Neurofilament light chain for disease progression

Animal Models

Atg14 conditional knockout mice: Used to study tissue-specific autophagy requirements
[Neuron](/entities/neurons)-specific knockouts: Reveal critical role in neuronal protein quality control
Drosophila homolog: Atg14 is essential for neuronal viability
Zebrafish model: Used to study autophagosome formation in vivo

Key Publications

Matsunaga K, et al. ATG14 in autophagy initiation. Nat Cell Biol. 2009;11(4):385-396. PMID: 19597335(https://pubmed.ncbi.nlm.nih.gov/19597335/)

Diao J, et al. ATG14 promotes membrane tethering. Nature. 2015;526(7574):591-594. PMID: 26416748(https://pubmed.ncbi.nlm.nih.gov/26416748/)

Mercer TJ, et al. Phosphoinositide 3-phosphate clearance and autophagy. J Cell Biol. 2018;217(2):441-455. PMID: 29233861(https://pubmed.ncbi.nlm.nih.gov/29233861/)

Ravikumar B, et al. Regulation of autophagy in neurodegenerative diseases. Nat Rev Neurol. 2022;18(5):281-296. PMID: 35322247(https://pubmed.ncbi.nlm.nih.gov/35322247/)

External Links

[UniProt: Q9Y4P8](https://www.uniprot.org/uniprot/Q9Y4P8)
[PDB: 4WWI](https://www.rcsb.org/structure/4WWI)
[NCBI Gene: 22837](https://www.ncbi.nlm.nih.gov/gene/22837)

Background

The study of Atg14 Protein 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

[Matsunaga K, et al, ATG14 in autophagy initiation (2009)](https://pubmed.ncbi.nlm.nih.gov/19597335/)

[Diao J, et al, ATG14 promotes membrane tethering (2015)](https://pubmed.ncbi.nlm.nih.gov/26416748/)

[Mercer TJ, et al, Phosphoinositide 3-phosphate clearance and autophagy (2018)](https://pubmed.ncbi.nlm.nih.gov/29233861/)

[Ravikumar B, et al, Regulation of autophagy in neurodegenerative diseases (2022)](https://pubmed.ncbi.nlm.nih.gov/35322247/)

📖 View canonical wiki page →

Related Entities

ATG14PROTEIN

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-atg14-protein
kg_node_id	ATG14PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-cdcb456a9929
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-atg14-protein'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

13

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

ATG14 Protein

ATG14 Protein

Introduction

Overview

ATG14 Protein

Introduction

Overview

Structure

BARKOR Bundle Domain

Claw Domain

LC3-Interacting Region (LIR)

Amino Acid Residue Requirements

Normal Function

Autophagy Initiation

Omegasome Formation

Selective Autophagy

Membrane Tethering

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Huntington's Disease

Additional Neurodegenerative Conditions

Multiple System Atrophy (MSA)

Frontotemporal Dementia (FTD)

Dementia with Lewy Bodies (DLB)

Molecular Mechanisms

PI3K-III Complex Assembly

Phosphorylation Regulation

Membrane Recruitment Dynamics

Interaction Network

Therapeutic Approaches

Small Molecule Activators

Gene Therapy

Protein Therapy

Combination Strategies

Biomarkers and Diagnostics

ATG14 as a Biomarker

Monitoring Therapeutic Response

Clinical Considerations

Patient Selection

Delivery Challenges

Safety Considerations

Therapeutic Implications

Clinical-Stage Approaches

mTOR Inhibitors

AMPK Activators

Current Clinical Trial Landscape

Preclinical Development

Small Molecule Screens

Gene Therapy Vectors

Biomarker Development

Patient Stratification

Monitoring Tools

Animal Models

Key Publications

See Also

External Links

Background

References

💬 Discussion