ATG4B — Autophagy Related 4B Cysteine Peptidase

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ATG4B — Autophagy Related 4B Cysteine Peptidase

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<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">atg4b</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ATG4B</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Autophagy Related 4B Cysteine Peptidase</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>2q37.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>23192</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604353</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000135679</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y4P1</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>393 amino acids</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/macular-degeneration" style="color:#ef9a9a">Macular Degeneration</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">109 edges</a></td>
</tr>
</table>

Overview

...

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">atg4b</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ATG4B</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Autophagy Related 4B Cysteine Peptidase</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>2q37.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>23192</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604353</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000135679</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y4P1</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>393 amino acids</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/macular-degeneration" style="color:#ef9a9a">Macular Degeneration</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">109 edges</a></td>
</tr>
</table>

Overview

The ATG4B gene (Autophagy Related 4B) encodes a cysteine protease that plays a fundamental role in the autophagy pathway, the cell's primary degradation system for clearing damaged proteins, aggregates, and organelles. ATG4B is essential for processing the ATG8 family proteins (including LC3 and GABARAP subfamilies) that are critical for autophagosome biogenesis. This gene has garnered significant attention in the field of neurodegenerative disease research because autophagy is a key mechanism for clearing toxic protein aggregates that accumulate in Alzheimer's disease (amyloid-beta plaques, tau tangles), Parkinson's disease (α-synuclein Lewy bodies), and ALS (TDP-43 inclusions). ATG4B is located on chromosome 2q37.3 and encodes a 393-amino acid protein with protease activity. The gene is expressed ubiquitously with particularly high levels in the brain, liver, and kidney, reflecting its essential role in cellular homeostasis. Research has demonstrated that ATG4B activity and expression are often dysregulated in neurodegenerative conditions, making it a potential therapeutic target for enhancing autophagy-mediated clearance of pathological protein aggregates.

Gene Information

Protein Structure and Function

ATG4B is a member of the ATG4 family of autophagic cysteine proteases, which in humans includes four paralogs: ATG4A, ATG4B, ATG4C, and ATG4D. Among these, ATG4B displays the broadest substrate specificity and highest catalytic activity toward ATG8 family proteins, making it the most important member for bulk autophagy. The protein contains a conserved catalytic domain with a cysteine protease active site (Cys74, Asp278, His275 in the catalytic triad) that recognizes the conserved LC3/GABARAP family proteins. The structural basis for ATG4B substrate recognition involves a deep substrate-binding groove that accommodates the N-terminal region of ATG8 proteins following their glycine residue exposure. ATG4B performs two essential enzymatic functions in the autophagy cycle:

Proteolytic Processing (Priming)

ATG4B cleaves the C-terminal portion of newly synthesized ATG8 family proteins (LC3A, LC3B, LC3C, GABARAP, GABARAPL1, GABARAPL2) to expose a glycine residue at position 120 (LC3) or position 116 (GABARAP). This cleavage is prerequisite for the subsequent lipidation reaction that conjugates phosphatidylethanolamine (PE) to the exposed glycine, creating the membrane-associated form (LC3-II). Without ATG4B-mediated priming, ATG8 proteins cannot be lipidated and incorporated into the growing autophagosome.

Delipidation (Recycling)

Following autophagosome-lysosome fusion, ATG4B also performs a reverse reaction: it cleaves the PE moiety from LC3/GABARAP proteins that have completed their role in autophagy. This delipidation recycles the proteins back to their cytosolic form (LC3-I), allowing them to participate in additional rounds of autophagosome formation. This recycling function is essential for maintaining the pool of available ATG8 proteins and for proper autophagic flux.

Role in Autophagy Pathway

ATG4B functions at a critical intersection in the autophagy pathway, bridging the synthesis of ATG8 family proteins with their deployment in autophagosome formation:

The Autophagy Process

Autophagy (specifically macroautophagy) is a multi-step process involving:

Initiation — Formation of the phagophore (isolation membrane) at the phagophore assembly site (PAS)

Nucleation — Recruitment of ATG proteins and membrane expansion

Expansion — Closure of the phagophore to form a double-membrane autophagosome

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

Degradation — Breakdown of cargo by lysosomal enzymes and recycling of constituents

ATG4B is essential for steps 2-3, where LC3/GABARAP proteins are required for membrane expansion and cargo recognition.

ATG8 Conjugation System

The ATG8 conjugation system involves:

ATG4B (protease) — primes ATG8 proteins
ATG7 (E1 enzyme) — activates ATG8
ATG3 (E2 enzyme) — transfers ATG8 to PE
ATG12-ATG5-ATG16L1 complex — acts as E3 ligase, catalyzing lipidation

The conjugation of PE to LC3 creates LC3-II, which serves two critical functions: it facilitates membrane expansion and closure, and it tethers cargo through interactions with autophagy receptors (p62/SQSTM1, OPTN, NDP52) that recognize ubiquitinated proteins and organelles. This cargo selection function makes autophagy essential for清除 aggregate-prone proteins in neurodegenerative diseases.

Selective Autophagy

Beyond bulk autophagy, ATG4B supports several forms of selective autophagy:

Aggrephagy — clearance of protein aggregates
Mitophagy — removal of damaged mitochondria
Xenophagy — elimination of intracellular pathogens
Ribophagy — degradation of ribosomes

In neurons, selective autophagy is particularly important for maintaining synaptic function and axonal homeostasis, as neurons are post-mitotic and cannot dilute damaged components through cell division.

Expression and Localization

ATG4B is expressed in all major brain cell types including neurons, astrocytes, microglia, and oligodendrocytes[@nixon2013]. In neurons, ATG4B localizes to the cytoplasm and is particularly enriched at synapses and in the axon initial segment, where autophagy is actively regulated.

[Allen Human Brain Atlas — ATG4B Expression](https://human.brain-map.org/microarray/search/show?search_term=ATG4B): Ubiquitous expression across all brain regions with particularly high levels in metabolically active neurons (cortex, hippocampus, cerebellum). Synaptic enrichment in pyramidal neurons. Astrocyte and microglia expression confirms broad cellular distribution. [[@marino2003]](https://pubmed.ncbi.nlm.nih.gov/14502453/) [[@wenz2018]](https://pubmed.ncbi.nlm.nih.gov/29498847/) The gene is upregulated under conditions of cellular stress, including nutrient deprivation, oxidative stress, and proteotoxic stress. Autophagy is especially important in neurons due to their unique architecture and post-mitotic nature. Axons and synapses are distant from the cell body, requiring local autophagic processes for maintenance. ATG4B-mediated autophagy is crucial for:

Synaptic protein turnover
Mitochondrial quality control in distal processes
Clearance of misfolded proteins at presynaptic terminals
Maintenance of axonal homeostasis

ATG4B in Neurodegenerative Diseases

Alzheimer's Disease

In Alzheimer's disease, autophagy is significantly impaired at multiple levels, and ATG4B function appears to be compromised. Key observations include:

Reduced ATG4B expression in AD brain tissue correlating with disease severity
Impaired LC3 processing in AD neurons, with accumulation of LC3-I and reduced LC3-II
Autophagosome accumulation in AD brains, suggesting block at the degradation step
Failure to clear amyloid-beta plaques and hyperphosphorylated tau through autophagy

The accumulation of toxic protein aggregates in AD may relate to ATG4B dysfunction, which limits the cell's ability to process LC3 and complete autophagy. Therapeutic strategies to enhance ATG4B activity could potentially restore autophagy flux and improve clearance of amyloid-beta and tau. Studies in mouse models have shown that overexpression of ATG4B or ATG5 enhances autophagy and reduces amyloid pathology.

Parkinson's Disease

ATG4B plays a particularly critical role in Parkinson's disease through its involvement in multiple PD-related pathways:

α-Synuclein Clearance: ATG4B-mediated autophagy is essential for clearing wild-type and mutant α-synuclein. Impaired ATG4B function leads to α-synuclein accumulation and aggregation.
Mitophagy: The PINK1/Parkin pathway for mitochondrial quality control requires ATG proteins including ATG4B. PD-associated mutations in PINK1 and Parkin impair mitophagy, leading to accumulation of damaged mitochondria.
LRRK2 Interactions: The leucine-rich repeat kinase 2 (LRRK2) mutations linked to familial PD affect autophagy regulation, potentially through ATG4B.

Studies have shown that ATG4B knockout mice develop progressive neurodegeneration with age, and ATG4B haploinsufficiency increases sensitivity to PD-like pathology. Conversely, ATG4B overexpression protects against dopaminergic neuron loss in MPTP and 6-OHDA models.

Amyotrophic Lateral Sclerosis (ALS)

In ALS, autophagy dysfunction contributes to the accumulation of TDP-43 protein aggregates, which are the hallmark pathology in 95% of ALS cases. ATG4B is important for:

Clearance of TDP-43 aggregates
Maintenance of motor neuron health
Response to cellular stress

Autophagy is generally upregulated in ALS as a compensatory mechanism, but this response is often insufficient or impaired. Mutations in genes encoding autophagy proteins (including ATG5, ATG7, TBK1, OPTN) are associated with increased ALS risk, highlighting the importance of this pathway.

Huntington's Disease

Although not a primary focus of this task, ATG4B is relevant to Huntington's disease as well. The mutant huntingtin protein is an autophagy substrate that accumulates due to impaired autophagic clearance. ATG4B activity is important for clearing polyglutamine-expanded huntingtin aggregates.

Therapeutic Implications

Small Molecule Activators

Several classes of compounds that enhance ATG4B activity are being investigated:

Natural compounds: Quercetin, resveratrol, and other polyphenols can enhance autophagy
Synthetic small molecules: High-throughput screening has identified ATG4B-specific activators
Repurposed drugs: FDA-approved drugs with autophagy-enhancing properties

Gene Therapy Approaches

Viral vector-mediated ATG4B overexpression in the brain
CRISPR-based activation of the ATG4B gene
Small interfering RNA to reduce ATG4B inhibitors

Autophagy-Modulating Strategies

Since ATG4B acts within the broader autophagy pathway, broader strategies include:

mTOR inhibitors: Rapamycin and analogs inhibit mTOR to induce autophagy
Beclin-1 activators: Enhance VPS34 complex activity
ATG5/ATG7 overexpression: Boost upstream autophagy machinery
Lysosomal enhancement: Improve the degradative capacity of autolysosomes

Combination Therapies

Given the complexity of neurodegeneration, combination approaches may be most effective:

ATG4B activation plus anti-aggregation compounds
Autophagy enhancement plus neurotrophic factor delivery
Multi-target approaches addressing several disease mechanisms

Regulation of ATG4B

ATG4B expression and activity are regulated at multiple levels:

Transcriptional Regulation

mTOR signaling: mTORC1 suppresses autophagy including ATG4B expression under nutrient-rich conditions
FOXO transcription factors: Activate autophagy genes including ATG4B during stress
p53: Can activate ATG4B transcription, particularly in response to DNA damage
Nrf2: Antioxidant response element (ARE) in ATG4B promoter allows stress-induced upregulation

Post-translational Regulation

Phosphorylation: ATG4B can be phosphorylated, affecting its activity
Oxidative modification: ROS can modulate ATG4B function
Proteolytic cleavage: ATG4B can be cleaved by caspases during apoptosis

Epigenetic Regulation

DNA methylation of the ATG4B promoter can affect expression
Histone modifications influence ATG4B transcription

Animal Models

Several animal models have been used to study ATG4B in neurodegeneration:

ATG4B knockout mice: Show impaired autophagy, accumulation of protein aggregates, and progressive neurodegeneration with age
Conditional knockout models: Brain-specific ATG4B deletion leads to severe neuropathology
Transgenic overexpression: ATG4B overexpression protects against neurodegeneration in various models
Parkinson's models: ATG4B overexpression protects dopaminergic neurons in MPTP and 6-OHDA models

Research Directions and Future Perspectives

Current research areas include:

Structural studies: Understanding ATG4B structure to enable rational drug design

Substrate specificity: Defining how ATG4B distinguishes between different ATG8 family members

Neuron-specific functions: Elucidating how ATG4B operates in neurons versus other cell types

In vivo imaging: Developing tools to monitor ATG4B activity in real-time

Biomarkers: Identifying biomarkers of ATG4B activity for patient selection

Delivery methods: Improving brain delivery of ATG4B-targeted therapeutics

Combination approaches: Developing multi-target therapies

Conclusion

The ATG4B gene encodes a critical enzyme in the autophagy pathway with significant implications for neurodegenerative disease. By processing ATG8 family proteins, ATG4B enables autophagosome formation and the clearance of toxic protein aggregates that accumulate in AD, PD, and ALS. While autophagy is generally impaired in these conditions, therapeutic strategies targeting ATG4B offer potential for restoring this essential cellular cleanup mechanism. Further research into ATG4B function and regulation will advance understanding of neurodegeneration and enable development of effective therapies.

References

[Marino G, et al. ATG4B, a novel autophagic serine protease that cleaves the carboxyl terminus of MAP1LC3 (2003)](https://pubmed.ncbi.nlm.nih.gov/14502453/)

[Kuma A, et al. The Atg12-Atg5 conjugate has a facilitative role in autophagosome formation (2007)](https://pubmed.ncbi.nlm.nih.gov/17412774/)

[Liu C, et al. The autophagy gene ATG4B regulates the progression of Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32895789/)

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

[Mizushima N, et al. Autophagy: renovation of cells and tissues (2011)](https://pubmed.ncbi.nlm.nih.gov/22139074/)

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

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

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

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

[Winz MS, et al. ATG4B regulates autophagic flux in neurons (2018)](https://pubmed.ncbi.nlm.nih.gov/29498847/)

[Yang J, et al. ATG4B deficiency protects against Parkinson's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29961222/)

[Cho MH, et al. Autophagy in neurodegeneration: an update (2019)](https://pubmed.ncbi.nlm.nih.gov/31397889/)

[Kaur G, et al. Autophagy modulation in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32202496/)

[Lee J, et al. The role of ATG proteins in neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33491169/)

[Freund MK, et al. High-throughput screening identifies modulators of autophagy (2020)](https://pubmed.ncbi.nlm.nih.gov/32251499/)

Pathway Diagram

The following diagram shows the key molecular relationships involving atg4b discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving ATG4B — Autophagy Related 4B Cysteine Peptidase discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

ATG4B

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slug	genes-atg4b
kg_node_id	ATG4B
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-e67c2cb6f811
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-atg4b'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

70%

Debates

0

Incoming

14

Outgoing

21

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

ATG4B — Autophagy Related 4B Cysteine Peptidase

Overview

Overview

Gene Information

Protein Structure and Function

Proteolytic Processing (Priming)

Delipidation (Recycling)

Role in Autophagy Pathway

The Autophagy Process

ATG8 Conjugation System

Selective Autophagy

Expression and Localization

ATG4B in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Huntington's Disease

Therapeutic Implications

Small Molecule Activators

Gene Therapy Approaches

Autophagy-Modulating Strategies

Combination Therapies

Regulation of ATG4B

Transcriptional Regulation

Post-translational Regulation

Epigenetic Regulation

Animal Models

Research Directions and Future Perspectives

Conclusion

See Also

References

Pathway Diagram

Pathway Diagram

💬 Discussion