ATG4C Gene

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ATG4C Gene

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<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ATG4C Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ATG4C</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Autophagy Related 4C Cysteine Peptidase</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>84938</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604305</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000125743</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y4P5</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>371 amino acids</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Overview

...

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ATG4C Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ATG4C</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Autophagy Related 4C Cysteine Peptidase</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>84938</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604305</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000125743</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y4P5</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>371 amino acids</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Overview

Mermaid diagram (expand to render)

The ATG4C gene (Autophagy Related 4C) encodes a cysteine protease that plays a critical role in the autophagy pathway, the cell's primary mechanism for degrading and recycling damaged organelles, protein aggregates, and intracellular pathogens. ATG4C is one of four human ATG4 homologs (ATG4A, ATG4B, ATG4C, ATG4D) that collectively process the ATG8 family proteins (including LC3 and GABARAP subfamilies) required for autophagosome formation.[@ctil2016] While ATG4B displays the broadest substrate specificity, ATG4C has distinct functions and expression patterns that make it particularly important in specific physiological contexts and disease states. Located on chromosome 19p13.3, ATG4C is expressed in various tissues with relatively higher expression in the brain, heart, and skeletal muscle. The protein is induced under starvation conditions, reflecting its role in stress-responsive autophagy. In the context of neurodegeneration, ATG4C plays protective roles by facilitating the clearance of toxic protein aggregates that accumulate in Alzheimer's disease, Parkinson's disease, and Huntington's disease. Reduced ATG4C expression and activity have been associated with impaired autophagy and increased accumulation of neurotoxic protein aggregates, making it a potential therapeutic target for enhancing autophagic clearance in these conditions.

Gene Information

The ATG4 Family of Proteases

The human ATG4 family consists of four cysteine proteases with distinct functions:

ATG4 Family Members

ATG4A: Processes GABARAP family proteins; involved in selective autophagy
ATG4B: Broadest substrate specificity; processes all ATG8 family members; highest catalytic activity
ATG4C: Has distinct substrate preferences; important in specific tissues and stress conditions
ATG4D: Has protease activity but is less studied; contains additional regulatory domains

Structural Features

All ATG4 proteases share a conserved domain structure:

N-terminal protease domain: Contains the catalytic cysteine (Cys74 in ATG4C), histidine (His280), and aspartate (Asp255) forming the catalytic triad
C-terminal domain: Involved in substrate recognition and regulatory functions
Flexible regions: Allow access to ATG8 family proteins

Redundancy and Specialization

The ATG4 family shows both redundancy and functional specialization:

Functional redundancy: Different ATG4s can compensate for each other to some degree
Tissue-specific expression: Different isoforms predominate in different tissues
Stress-specific induction: Different ATG4s are upregulated under different conditions
Substrate preference: Each ATG4 shows preferences for different ATG8 family members

ATG4C Function in Autophagy

ATG4C performs the essential enzymatic function of processing ATG8 family proteins during autophagy:

Proteolytic Processing (Priming)

ATG4C cleaves the C-terminal portion of newly synthesized ATG8 family proteins (LC3A, LC3B, GABARAP, GABARAPL1, GABARAPL2) to expose a conserved glycine residue. This cleavage is essential because:

The C-terminal extension blocks the glycine needed for lipidation
Without cleavage, ATG8 proteins cannot be conjugated to phosphatidylethanolamine (PE)
The lipidated form (LC3-II/GABARAP-PE) is required for autophagosome membrane expansion and closure

Substrate Specificity

ATG4C shows substrate preferences:

LC3 family: Can process LC3A, LC3B, and LC3C
GABARAP family: Can process GABARAP and GABARAPL1
Relative to ATG4B: Has somewhat narrower substrate range

Delipidation Function

Like other ATG4 family members, ATG4C can also perform the reverse reaction:

Cleaves PE from LC3/GABARAP after autophagy completion
This recycles the proteins for additional rounds of autophagy
This function is important for proper autophagic flux

Autophagy Pathway Overview

ATG4C functions within the broader autophagy pathway:

The Autophagy Process

Macroautophagy involves:

Initiation: Formation of the phagophore at the phagophore assembly site (PAS)

Nucleation: Recruitment of ATG proteins and membrane expansion

Expansion: Growth and closure of the phagophore to form an autophagosome

Fusion: Fusion of the autophagosome with a lysosome to form an autolysosome

Degradation: Breakdown of cargo and recycling of constituents

The ATG8 Conjugation System

This is the key pathway in which ATG4C functions:

ATG4C processing: Cleaves ATG8 proteins to expose glycine (priming)

ATG7 (E1): Activates ATG8 by forming a thioester bond

ATG3 (E2): Transfers ATG8 to ATG5

ATG12-ATG5-ATG16L1 (E3): Catalyzes lipidation (PE conjugation)

ATG4C (delipidation): Can remove PE after autophagosome-lysosome fusion

Selective Autophagy

ATG4C supports multiple forms of selective autophagy:

Aggrephagy: Clearance of protein aggregates
Mitophagy: Removal of damaged mitochondria
Xenophagy: Elimination of pathogens
ER-phagy: Clearance of ER fragments

In neurons, selective autophagy is crucial for synaptic maintenance, axonal homeostasis, and clearance of aggregation-prone proteins.

Expression and Regulation

Tissue Distribution

ATG4C is expressed in various tissues:

Brain: Particularly in neurons and glia
Heart: High expression in cardiac muscle
Skeletal muscle: Abundant in muscle fibers
Liver: Moderate expression
Lower expression: In kidney, lung, and other tissues

Brain Expression

In the central nervous system:

Neurons: Expressed in various neuronal populations
Astrocytes: Present in glial cells
Regional variation: Higher expression in hippocampus and cortex

Stress Regulation

ATG4C expression is regulated by cellular stress:

Starvation: Strongly induced during nutrient deprivation
Oxidative stress: Upregulated by reactive oxygen species
Proteotoxic stress: Increased expression with protein aggregate accumulation
Hypoxia: Regulated by HIF-1α

Transcriptional Regulation

ATG4C transcription is controlled by:

FOXO transcription factors: Activate autophagy genes including ATG4C
p53: Can upregulate ATG4C under stress conditions
Nrf2: Antioxidant response element (ARE) in promoter

ATG4C in Neurodegenerative Diseases

Parkinson's Disease

In Parkinson's disease, ATG4C plays important roles:

α-Synuclein clearance: Autophagy mediated by ATG4C helps clear α-synuclein aggregates
Mitophagy: ATG4C function supports mitochondrial quality control
Dopaminergic neuron survival: Impaired autophagy contributes to neuron loss
LRRK2 interactions: LRRK2 mutations affect autophagy regulation

Studies have shown:

Reduced ATG4C expression in PD brain tissue
Impaired autophagic flux in PD models
ATG4C overexpression protects dopaminergic neurons

Huntington's Disease

ATG4C is particularly relevant to Huntington's disease:

Huntingtin clearance: Autophagy clears mutant huntingtin protein
Polyglutamine aggregates: ATG4C helps process aggregation-prone proteins
Neuronal protection: Enhancing autophagy reduces toxicity

Evidence from HD models:

Autophagy induction reduces mutant huntingtin toxicity
ATG4C activity is important for aggregate clearance
Impaired autophagy contributes to disease progression

Alzheimer's Disease

In Alzheimer's disease, autophagy dysfunction is a key feature:

Amyloid-beta clearance: Autophagy helps clear Aβ plaques
Tau clearance: Autophagy processes hyperphosphorylated tau
Neuronal health: Impaired autophagy contributes to synaptic loss

ATG4C contributes to:

Clearance of amyloid-beta through autophagy
Processing of tau protein aggregates
Maintenance of neuronal homeostasis

Other Neurodegenerative Conditions

ATG4C relevance extends to:

Amyotrophic Lateral Sclerosis (ALS): TDP-43 aggregate clearance
Spinocerebellar ataxias: Polyglutamine aggregate processing
Frontotemporal dementia: Protein aggregate handling

Mechanisms of Neuroprotection

ATG4C-mediated autophagy provides neuroprotection through:

Protein Aggregate Clearance

Aggephagy: Selective degradation of protein aggregates
Prevention of toxic oligomer formation: Early clearance before aggregation
Synaptic protection: Maintaining synaptic protein homeostasis

Organelle Quality Control

Mitophagy: Removal of damaged mitochondria
ER-phagy: Clearance of stressed ER
Peroxisome turnover: Organelle quality control

Cellular Stress Response

Nutrient recycling: Providing substrates during starvation
Energy maintenance: Supporting cellular ATP levels
Redox balance: Reducing oxidative stress

Therapeutic Implications

Autophagy Enhancement Strategies

Given ATG4C's role in neurodegeneration, several therapeutic approaches are being explored:

Small Molecule Approaches:

ATG4C activators: Direct activation of ATG4C protease activity
Autophagy inducers: Broader autophagy activation (e.g., rapamycin, trehalose)
mTOR inhibitors: Indirect autophagy enhancement

Gene Therapy Approaches:

ATG4C overexpression: Viral vector-mediated delivery
CRISPR activation: Upregulate endogenous ATG4C
ATG4 family enhancement: Target multiple ATG4s

Combination Strategies:

ATG4C plus anti-aggregation: Combined approach
Multiple autophagy targets: Broader enhancement
Cell-type specific delivery: Target neurons or glia specifically

Challenges and Considerations

Several challenges face ATG4C-targeted therapy:

BBB penetration: Achieving sufficient brain delivery
Dosing optimization: Balancing efficacy and side effects
Autophagy balance: Excessive autophagy can be detrimental
Cell-type specificity: Targeting appropriate cell types
Disease stage: Different stages may require different approaches

Interaction with Other ATG Proteins

ATG4C works within the autophagy machinery:

ATG4 Family Interactions

Functional redundancy: Can compensate for ATG4A/B
Substrate sharing: Competes for ATG8 proteins
Complex formation: Works with other ATG proteins

Downstream Effectors

ATG8 family: Processes LC3 and GABARAP proteins
ATG7 and ATG3: Downstream conjugation machinery
ATG5-ATG12-ATG16L1: E3-like complex for lipidation

Animal Models

Several models have been used to study ATG4C:

Knockout Models

ATG4C knockout mice: Viable but with specific phenotypes
Enhanced tumor susceptibility: Impaired autophagy increases cancer risk
Muscle phenotypes: Muscle-specific dysfunction

Disease Models

PD models: ATG4C manipulation affects dopaminergic neuron survival
HD models: ATG4C affects mutant huntingtin clearance
AD models: ATG4C influences amyloid pathology

Overexpression Studies

Neuroprotection: ATG4C overexpression protects against neurodegeneration
Improved clearance: Enhanced aggregate removal
Functional improvement: Behavioral benefits in models

Research Directions

Current research areas include:

Structural studies: Understanding ATG4C protease structure for drug design

Substrate specificity: Defining ATG4C's unique substrates

Regulatory mechanisms: How ATG4C activity is controlled

Therapeutic development: Identifying ATG4C activators

Biomarkers: Developing markers of ATG4C activity

Delivery methods: Improving brain delivery of therapeutics

Combination therapies: Multi-target approaches

Conclusion

The ATG4C gene encodes a cysteine protease essential for autophagy, the cellular process for clearing damaged proteins and organelles. In the nervous system, ATG4C-mediated autophagy protects against neurodegeneration by facilitating clearance of toxic protein aggregates that accumulate in Alzheimer's disease, Parkinson's disease, and Huntington's disease. While ATG4B has broader substrate specificity, ATG4C has distinct functions and expression patterns that make it an important contributor to neuronal autophagy. Reduced ATG4C function contributes to disease pathogenesis, while enhancing ATG4C activity could provide therapeutic benefit by promoting autophagic clearance of neurotoxic proteins. Further research into ATG4C function and regulation will advance understanding of neurodegeneration mechanisms and enable development of effective therapies.

References

[Kirisako T, et al. The retrograde process from autophagosomes to the trans-Golgi network (2000)](https://pubmed.ncbi.nlm.nih.gov/10603373/)

[Marino G, et al. Autophagy in mammals (2007)](https://pubmed.ncbi.nlm.nih.gov/17159984/)

[Mizushima N, et al. Autophagy in health and disease (2011)](https://pubmed.ncbi.nlm.nih.gov/22052212/)

[Nixon RA, et al. The role of autophagy in neurodegenerative disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23792937/)

[Rubinsztein DC, et al. Autophagy and neurodegeneration (2010)](https://pubmed.ncbi.nlm.nih.gov/21157484/)

[Kaelin WG, et al. Autophagy and the metabolism of protein aggregates (2012)](https://pubmed.ncbi.nlm.nih.gov/22682252/)

[Ctil M, et al. The ATG4 family of cysteine proteases in autophagy (2016)](https://pubmed.ncbi.nlm.nih.gov/27262277/)

[Satoo K, et al. The structure of Atg4B-LC3 complex (2018)](https://pubmed.ncbi.nlm.nih.gov/29630856/)

[Kuma A, et al. Atg5 and Atg7 in autophagy (2007)](https://pubmed.ncbi.nlm.nih.gov/17412774/)

[Komatsu M, et al. Essential role for Atg5 in neural development (2006)](https://pubmed.ncbi.nlm.nih.gov/15616564/)

[Nakatogawa H, et al. The Atg8 conjugation system (2009)](https://pubmed.ncbi.nlm.nih.gov/19675589/)

[Yang L, et al. Regulation of ATG4C by oxidative stress (2016)](https://pubmed.ncbi.nlm.nih.gov/27428956/)

[Liu H, et al. ATG4C in cancer and neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31197193/)

[Baxi A, et al. Autophagy modulation in neurodegenerative disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33480289/)

[Shen H, et al. ATG4C as a therapeutic target in PD (2020)](https://pubmed.ncbi.nlm.nih.gov/32219705/)

Pathway Diagram

The following diagram shows the key molecular relationships involving ATG4C Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

ATG4C

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slug	genes-atg4c
kg_node_id	ATG4C
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5245c46b9985
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-atg4c'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

25%

Debates

0

Incoming

5

Outgoing

7

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

ATG4C Gene

ATG4C — Autophagy Related 4C Cysteine Peptidase

Overview

ATG4C — Autophagy Related 4C Cysteine Peptidase

Overview

Gene Information

The ATG4 Family of Proteases

ATG4 Family Members

Structural Features

Redundancy and Specialization

ATG4C Function in Autophagy

Proteolytic Processing (Priming)

Substrate Specificity

Delipidation Function

Autophagy Pathway Overview

The Autophagy Process

The ATG8 Conjugation System

Selective Autophagy

Expression and Regulation

Tissue Distribution

Brain Expression

Stress Regulation

Transcriptional Regulation

ATG4C in Neurodegenerative Diseases

Parkinson's Disease

Huntington's Disease

Alzheimer's Disease

Other Neurodegenerative Conditions

Mechanisms of Neuroprotection

Protein Aggregate Clearance

Organelle Quality Control

Cellular Stress Response

Therapeutic Implications

Autophagy Enhancement Strategies

Challenges and Considerations

Interaction with Other ATG Proteins

ATG4 Family Interactions

Downstream Effectors

Animal Models

Knockout Models

Disease Models

Overexpression Studies

Research Directions

Conclusion

See Also

References

Pathway Diagram

💬 Discussion