Gene: EPG5
UniProt: Q9H0C8
Molecular Weight: ~252 kDa
Subcellular Localization: Late endosomes, lysosomes, autophagosomes
Protein Family: EPG5/VIPAS39 family
EPG5 (Excessive Autophagy 5) is a key regulator of autophagy and lysosomal function. It plays a critical role in neuronal survival and has been implicated in various neurodegenerative diseases.
EPG5 is a large protein with multiple functional domains:
- N-terminal region: Contains multiple HEAT repeats
- C-terminal region: Features a Rab GTPase-activating protein (GAP) domain
- LIR (LC3-interacting region): Binds LC3/Atg8 proteins on autophagosomes
- VPS domain: Homology to vacuolar protein sorting (VPS) factors
The protein acts as a tether connecting autophagosomes to lysosomes.
EPG5 is essential for autophagy, particularly for the maturation of autophagosomes into autolysosomes:
- Autophagosome-lysosome fusion: EPG5 serves as a tethering factor, facilitating the fusion of late autophagosomes with lysosomes
- Selective autophagy: EPG5 is involved in the degradation of specific cargoes including mitochondria (mitophagy) and protein aggregates
- Neuronal homeostasis: Proper autophagic flux is crucial for neuronal survival due to the post-mitotic nature of neurons
- Synaptic function: Autophagy regulates synaptic protein turnover and presynaptic terminal function
- Protein quality control: EPG5 helps clear misfolded proteins and damaged organelles
- Autophagy impairment: EPG5 mutations disrupt autophagosome-lysosome fusion, leading to accumulation of dysfunctional autophagosomes
- Protein aggregate clearance: Impaired selective autophagy results in toxic protein aggregate buildup
- Motor neuron degeneration: Autophagy failure contributes to motor neuron death
- VCP mutations: ALS-associated VCP mutations also impair autophagy, similar to EPG5 dysfunction
- SPG15 (ZFYVE26/SPG15): EPG5 interacts with SPG15 protein; both regulate late endocytic/autophagic pathways
- Autophagic vacuolation: EPG5 deficiency causes accumulation of autophagic vacuoles
- alpha-synuclein clearance: Impaired autophagy may reduce clearance of α-synuclein aggregates
- Mitophagy: EPG5-mediated mitophagy is important for mitochondrial quality control in dopaminergic neurons
- Autophagy-lysosomal pathway: EPG5 dysfunction contributes to impaired Aβ and tau clearance
- Neuronal vulnerability: Autophagy defects in AD neurons resemble EPG5-deficient cells
- Recessive disorder: Biallelic EPG5 mutations cause Vici syndrome, a severe multisystem disorder
- Neurodegeneration: Patients show profound neurodevelopmental impairment and neurodegeneration
| Approach |
Target |
Status |
| Gene therapy |
AAV-EPG5 delivery |
Preclinical |
| Autophagy enhancers |
Rapamycin, trehalose |
Research |
| Lysosomal function modulators |
Small molecules |
Discovery |
| Protein aggregate clearance |
ASO targeting aggregates |
Research |
This page was created as part of the NeuroWiki protein page initiative for neurodegeneration research.