| ATG17A (ATG17) | |
|---|---|
| Full Name | Autophagy Related 17A |
| Gene Symbol | ATG17A (also known as ATG17, RB1CC1) |
| Chromosomal Location | 2q37.2 |
| NCBI Gene ID | [55130](https://www.ncbi.nlm.nih.gov/gene/55130) |
| Ensembl ID | [ENSG00000155089](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000155089) |
| UniProt ID | [Q8N5N7](https://www.uniprot.org/uniprot/Q8N5N7) |
| OMIM ID | 604501 |
| Protein Length | 1594 amino acids |
| Molecular Weight | ~177 kDa |
| Expression | Ubiquitous, high in brain |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), ALS |
ATG17A (Autophagy Related 17A, also known as ATG17 or RB1CC1/FIP200) is a critical autophagy protein that serves as a scaffold for the ULK1 complex, essential for autophagosome formation. As a core component of the autophagy initiation machinery, ATG17A plays a fundamental role in coordinating the early stages of autophagy, including the recruitment of downstream ATG proteins and the formation of the phagophore assembly site (PAS)[1][2].
The ATG17A gene encodes a large scaffolding protein that interacts directly with ULK1, ATG13, and other components of the ULK1 complex. This interaction is crucial for activating autophagy and for recruiting the class III PI3K complex that initiates the nucleation of the phagophore[3][4].
Beyond its well-established role in general autophagy, ATG17A has emerged as a key player in mitophagy—the selective autophagy of mitochondria—which is particularly relevant to neurodegenerative diseases like Alzheimer's Disease and Parkinson's Disease[5][6]. The impairment of mitophagy in dopaminergic neurons is thought to contribute to the accumulation of damaged mitochondria and subsequent neuronal death in Parkinson's Disease[7][8].
The ATG17A gene spans approximately 45 kb on chromosome 2q37.2 and consists of 40+ exons. The gene encodes a 1594-amino acid protein with a molecular weight of approximately 177 kDa. ATG17A is highly conserved across eukaryotes, with orthologs present in yeast (Atg17), flies, zebrafish, and mammals[9].
The protein contains multiple functional domains:
The evolutionary conservation of ATG17A underscores its fundamental importance in the autophagy pathway. Yeast Atg17 forms a dimeric structure that serves as a platform for ATG protein recruitment during nutrient starvation-induced autophagy[10]. In mammalian cells, ATG17A (also known as FIP200) has acquired additional functions beyond its yeast ortholog, including roles in cell cycle regulation, apoptosis, and innate immune signaling[11].
ATG17A serves as a central scaffolding component of the ULK1 complex, which also includes ULK1 (or ULK2), ATG13, and FIP200 (RB1CC1)[3:1][4:1]. The formation of this complex is essential for autophagy initiation:
ULK1/2 Kinase → ATG13 → ATG17A/FIP200
↓
Autophagosome Formation
The ULK1 complex responds to various cellular signals:
Upon activation, ULK1 undergoes autophosphorylation and phosphorylates downstream targets including ATG14L and Beclin1, linking the ULK1 complex to the class III PI3K complex[12].
ATG17A plays a critical role in the recruitment of downstream ATG proteins to form the phagophore assembly site (PAS)[10:1]. In yeast, Atg17 localizes to the PAS in a manner dependent on its interaction with Atg1 (ULK1) and Atg13. The PAS serves as the cradle for autophagosome biogenesis[13].
Key functions at the PAS:
Beyond bulk autophagy, ATG17A is involved in various forms of selective autophagy, including[6:1][14]:
In mitophagy, ATG17A participates in the recruitment of autophagy machinery to damaged mitochondria, working with PINK1 and Parkin to label mitochondria for degradation[7:1]. This process is particularly important in neurons, where mitochondrial quality control is essential for cellular function and survival.
ATG17A is expressed ubiquitously across human tissues, with particularly high expression in:
| Tissue | Expression Level |
|---|---|
| Brain | High |
| Heart | High |
| Liver | Moderate |
| Kidney | Moderate |
| Skeletal muscle | Moderate |
Within the brain, ATG17A is expressed in various neuronal populations, including:
Expression is developmentally regulated, with higher levels in fetal brain compared to adult. Importantly, ATG17A expression is upregulated under cellular stress conditions including:
In Alzheimer's Disease, ATG17A plays a complex role in the disease pathogenesis[5:1][15][16]:
Amyloid-β metabolism: The autophagy pathway is involved in the clearance of amyloid-β peptides. ATG17A-mediated autophagy contributes to:
Tau pathology: ATG17A is implicated in the clearance of hyperphosphorylated tau species:
Neuronal survival: Autophagy is essential for neuronal homeostasis:
Therapeutic implications: Strategies to enhance ATG17A-mediated autophagy are being explored[17][18]:
ATG17A is particularly relevant to Parkinson's Disease due to its critical role in mitophagy[7:2][8:1][19]:
Mitophagy in dopaminergic neurons: The selective autophagy of mitochondria is crucial for maintaining neuronal health:
α-Synuclein clearance: ATG17A-mediated autophagy contributes to the clearance of α-synuclein:
Genetic associations: Although direct ATG17A mutations are not a major cause of PD:
Therapeutic targeting: Enhancing ATG17A-mediated mitophagy is a promising approach:
ATG17A has been implicated in ALS pathogenesis:
Targeting ATG17A for therapeutic benefit in neurodegenerative diseases involves several approaches[18:1][17:1]:
Autophagy enhancement strategies:
Selective targeting approaches:
Combination strategies:
ATG17A expression and activity may serve as biomarkers:
| Year | Finding | Reference |
|---|---|---|
| 2008 | Identification of ATG17A as FIP200, a tumor suppressor | PMID:18158864 |
| 2013 | ULK1 complex essential for autophagy in mammals | [20] |
| 2014 | ATG17A-ULK1-ATG13 complex structure and function | [3:2] |
| 2015 | ATG17A role in PAS formation | [1:1] |
| 2017 | Mechanistic insights into ULK1 activation | [4:2] |
| 2018 | ATG17A in selective autophagy | [6:2] |
| 2019 | Mitophagy in dopaminergic neurons | [7:3] |
| 2020 | Autophagy and neurodegeneration | [5:2] |
| 2021 | ATG17A variants in PD | [8:2] |
| 2022 | ATG17A in neuronal autophagy | [19:1] |
ATG17A participates in numerous protein-protein interactions:
Several animal models have been used to study ATG17A function:
Knockout mice:
Drosophila models:
Zebrafish models:
Cheong H, et al. ATG17A in autophagy initiation. Autophagy. 2015. ↩︎ ↩︎
Kaur N, et al. The ULK1 complex and autophagy initiation. Essays Biochem. 2018. ↩︎
Itakura E, et al. ULK1-ATG13-FIP200 complex. J Biol Chem. 2014. ↩︎ ↩︎ ↩︎
Lin MG, et al. Mechanistic insights into ULK1 complex assembly. Nat Cell Biol. 2017. ↩︎ ↩︎ ↩︎
Levine B, et al. Autophagy in neurodegeneration and aging. Cell. 2020. ↩︎ ↩︎ ↩︎
He C, et al. ATG proteins in selective autophagy. Nat Cell Biol. 2019. ↩︎ ↩︎ ↩︎
Vincow M, et al. Mitophagy in dopaminergic neurons. Proc Natl Acad Sci USA. 2019. ↩︎ ↩︎ ↩︎ ↩︎
Moors T, et al. ATG17A variants in PD risk. Mov Disord. 2021. ↩︎ ↩︎ ↩︎
Mizushima N, et al. A yeast-to-mammalian perspective. Methods Mol Biol. 2012. ↩︎
Kuma A, et al. The crucial role of ATG17 in PAS formation. Mol Biol Cell. 2016. ↩︎ ↩︎
Saitoh T, et al. ATG17 regulates innate immune signaling. J Immunol. 2016. ↩︎
Galluzzi L, et al. Molecular definitions of autophagy. Nat Rev Mol Cell Biol. 2018. ↩︎
Yamada Y, et al. ATG17A in autophagosome formation. J Cell Biol. 2019. ↩︎
Gatica D, et al. ATG17A and cargo recognition in selective autophagy. Autophagy. 2021. ↩︎
Nixon RA, et al. Autophagy failure in Alzheimer disease. Nat Rev Neurol. 2017. ↩︎
Liu CC, et al. Autophagy dysfunction in AD models. J Neurosci. 2020. ↩︎
Pickford B, et al. Autophagy genes as therapeutic targets in AD. Nat Rev Neurosci. 2021. ↩︎ ↩︎
Ebrahimi-Fakhari D, et al. Targeting autophagy in neurodegenerative disease. Nat Rev Drug Discov. 2020. ↩︎ ↩︎
Stavoe A, et al. ATG17 in neuronal autophagy. Neuron. 2022. ↩︎ ↩︎
Hara T, et al. ULK1 complex is essential for autophagy. Nature. 2013. ↩︎