<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.
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 constituentsThe 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 fusionSelective 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 approachesConclusion
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.
See Also
- [Autophagy](/mechanisms/autophagy)
- [ATG4B Gene](/genes/atg4b)
- [ATG4A Gene](/genes/atg4a)
- [LC3 Protein](/proteins/lc3-protein)
- [GABARAP Protein](/proteins/gabarap-protein)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Huntington's Disease](/diseases/huntingtons)
- [Protein Aggregation](/mechanisms/protein-aggregation)
- [Selective Autophagy](/mechanisms/selective-autophagy)
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)