ATG4C Protein
Overview
ATG4C (Autophagy-Related Protein 4C), also known as AUTL2 (Autophagy-Related Protein-Like 2) or cysteine protease ATG4C, is a cysteine protease that plays a critical role in autophagy, a fundamental cellular housekeeping process essential for neuronal survival and protein quality control. ATG4C belongs to the ATG4 family of proteases, which includes four mammalian homologs (ATG4A, ATG4B, ATG4C, and ATG4D), each with overlapping yet distinct cellular functions. This protease is particularly important in post-mitotic neurons, where accumulated misfolded proteins and dysfunctional organelles must be continuously cleared to maintain cellular homeostasis. ATG4C is encoded by the ATG4C gene located on chromosome 2q31.1 in humans, and its dysregulation has been implicated in multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
Function/Biology
...ATG4C Protein
Overview
ATG4C (Autophagy-Related Protein 4C), also known as AUTL2 (Autophagy-Related Protein-Like 2) or cysteine protease ATG4C, is a cysteine protease that plays a critical role in autophagy, a fundamental cellular housekeeping process essential for neuronal survival and protein quality control. ATG4C belongs to the ATG4 family of proteases, which includes four mammalian homologs (ATG4A, ATG4B, ATG4C, and ATG4D), each with overlapping yet distinct cellular functions. This protease is particularly important in post-mitotic neurons, where accumulated misfolded proteins and dysfunctional organelles must be continuously cleared to maintain cellular homeostasis. ATG4C is encoded by the ATG4C gene located on chromosome 2q31.1 in humans, and its dysregulation has been implicated in multiple neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
Function/Biology
ATG4C functions as a protease with two primary enzymatic activities critical for autophagy regulation. First, it acts as a deconjugase that cleaves the C-terminal tail of LC3 (light chain 3) protein, a key autophagy marker, removing it from its conjugated form on autophagosomal membranes. This deconjugation activity is essential for autophagy completion and recycling of LC3 molecules for subsequent rounds of autophagy. Second, ATG4C exhibits conjugase activity by catalyzing the cleavage of the C-terminal diglycine motif of nascent LC3-I, generating LC3-II, which is the lipidated form required for autophagosome formation. These proteolytic activities make ATG4C a rate-limiting enzyme in the autophagic cascade.
The enzymatic activity of ATG4C is regulated by cellular redox status. The catalytic cysteine residue (Cys81 in human ATG4C) is sensitive to oxidative modifications, allowing the protease to sense cellular stress conditions and adjust autophagy flux accordingly. Unlike ATG4B, which is constitutively active, ATG4C expression is more tightly controlled and responds dynamically to cellular conditions, suggesting specialized functions in particular cell types or stress contexts.
Role in Neurodegeneration
Impaired autophagy, particularly defects in ATG4C-mediated LC3 processing, contributes to pathological hallmarks of neurodegenerative diseases. In Alzheimer's disease, reduced autophagy flux promotes amyloid-beta accumulation and tau phosphorylation, both pathological features of the disease. Diminished ATG4C activity compromises the clearance of aggregation-prone proteins, allowing toxic oligomers to accumulate in neurons.
In Parkinson's disease, ATG4C dysfunction impairs the selective autophagy pathway (mitophagy) required for degrading damaged mitochondria. Alpha-synuclein aggregates, the hallmark pathology of Parkinson's disease, accumulate more readily when ATG4C-mediated autophagy is compromised. Studies have shown that age-related decline in ATG4C expression correlates with progressive neurodegeneration in Parkinson's models.
In ALS and frontotemporal dementia, dysregulation of ATG4C contributes to the accumulation of pathological protein inclusions containing TAU, FUS, or TDP-43. These aggregates are particularly neurotoxic in the motor neurons and frontotemporal cortex, suggesting that restoring ATG4C function could slow disease progression.
Molecular Mechanisms
ATG4C operates within the ULK1-BECN1-PIK3C3 initiation complex that nucleates autophagy. Upon activation, ATG4C processes LC3 precursors and catalyzes the lipidation of LC3-II with phosphatidylethanolamine (PE), enabling its incorporation into nascent autophagosomal membranes. The protease also interacts with WIPI proteins and ATG9, components of the autophagosome assembly machinery.
ATG4C regulation involves both transcriptional and post-translational mechanisms. TFEB (transcription factor EB) and FOXO transcription factors upregulate ATG4C gene expression during starvation and cellular stress. Phosphorylation by mTORC1 and proteolytic cleavage modulate ATG4C stability and localization. Notably, ATG4C contains a mitochondrial targeting sequence, allowing it to regulate mitophagy selectively at the mitochondrial membrane.
Clinical/Research Significance
Emerging evidence suggests ATG4C could be a therapeutic target in neurodegenerative diseases. Small molecules enhancing ATG4C protease activity or stabilizing the protein could restore autophagy flux and reduce pathological protein accumulation. Additionally, ATG4C expression levels in cerebrospinal fluid or blood biomarkers may help stratify patients and predict disease progression in Alzheimer's and Parkinson's disease populations.