RB1CC1 Gene
Introduction
Pathway Diagram
Mermaid diagram (expand to render)
The RB1CC1 (RB1-Inducible Coiled-Coil 1) gene, also known as FIP200 (Focal Adhesion Kinase Family Interacting Protein of 200 kDa), encodes a large scaffolding protein that plays essential roles in [autophagy](/mechanisms/autophagy), mitophagy, cell cycle regulation, and tumor suppression. RB1CC1 is a critical component of the ULK1 (Unc-51-Like Kinase 1) complex that initiates autophagosome formation, making it fundamental to cellular protein quality control mechanisms in neurons.
<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">RB1CC1 - RB1 Inducible Coiled-Coil 1 (FIP200)</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>RB1CC1</td></tr>
<tr><td><strong>Alternative Names</strong></td><td>FIP200, Focal Adhesion Kinase Interacting Protein</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>8q11.23</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td><a href="https://www.ncbi.nlm.nih.gov/gene/9821" target="_blank">9821</a></td></tr>
<tr><td><strong>OMIM</strong></td><td><a href="https://www.omim.org/entry/606082" target="_blank">606082</a></td></tr>
<tr><td><strong>Ensembl ID</strong></td><td><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000051596" target="_blank">ENSG00000051596</a></td></tr>
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprotkb/Q8TDW5/entry" target="_blank">Q8TDW5</a></td></tr>
<tr><td><strong>Protein Length</strong></td><td>1,894 amino acids</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Breast Cancer, ALS, FTD, Alzheimer's Disease, Parkinson's Disease</td></tr>
</table>
</div>
Summary
The RB1CC1 gene encodes a pivotal scaffolding protein that serves as the mammalian ortholog of yeast Atg17 in the autophagy initiation machinery. As the core component of the ULK1 complex (ULK1-ATG13-RB1CC1-ATG101), RB1CC1 is absolutely essential for autophagosome formation under both basal and stress-induced conditions.
In neurons, RB1CC1/FIP200 is particularly crucial due to the post-mitotic nature of neurons and their reliance on efficient protein quality control systems. Neurons are highly sensitive to the accumulation of misfolded proteins and damaged organelles, making autophagy an essential survival mechanism. RB1CC1-mediated autophagy clears protein aggregates (including [alpha-synuclein](/proteins/alpha-synuclein) and [tau](/proteins/tau-protein)), removes damaged mitochondria through mitophagy, and maintains synaptic homeostasis.
Dysregulation of RB1CC1 has been directly implicated in multiple neurodegenerative diseases including Alzheimer's disease ([AD](/diseases/alzheimers-disease)), [Parkinson's disease](/diseases/parkinsons-disease), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Mouse models with neuronal RB1CC1 deficiency develop progressive neurodegeneration with accumulation of p62/SQSTM1-positive protein aggregates.
The ULK1 Complex and Autophagy Initiation
RB1CC1/FIP200 forms the backbone of the ULK1 complex, which consists of four core components:
ULK1 (Unc-51-Like Autophagy-Activating Kinase 1) - The catalytic kinase that initiates autophagy
ATG13 - The regulatory subunit that bridges ULK1 to RB1CC1
RB1CC1/FIP200 - The scaffolding protein that oligomerizes and recruits the complex to phagophores
ATG101 - The stabilizer that prevents ATG13 degradationThe ULK1 complex serves as the master regulator of autophagosome formation, integrating signals from mTORC1 and AMPK. Once activated, ULK1 phosphorylates multiple substrates including ATG14L, ATG13, RB1CC1, and p62/SQSTM1.
Role in Mitophagy
Mitophagy—the selective autophagy of mitochondria—is particularly important in neurons due to their high metabolic demand and susceptibility to mitochondrial dysfunction. RB1CC1 plays a central role in mitophagy through PINK1-Parkin-dependent mechanisms:
Mitochondrial damage leads to stabilization of PINK1 on the outer mitochondrial membrane
PINK1 phosphorylates ubiquitin and Parkin
Phosphorylated Parkin ubiquitinates mitochondrial proteins
Autophagy receptors including p62/SQSTM1 recognize ubiquitinated mitochondria
RB1CC1-containing ULK1 complexes are recruited to damaged mitochondria
Autophagosomes engulf and fuse with lysosomesGiven the central role of mitochondrial dysfunction in [Parkinson's disease](/diseases/parkinsons-disease), RB1CC1-mediated mitophagy is highly relevant to PD pathogenesis.
Disease Associations
Alzheimer's Disease
In [Alzheimer's disease](/diseases/alzheimers-disease), RB1CC1 dysfunction contributes to:
- Amyloid and tau pathology via impaired autophagy
- Synaptic loss from disrupted protein homeostasis
- Mitochondrial dysfunction from reduced mitophagy
Parkinson's Disease
RB1CC1-mediated mitophagy is directly relevant to [PD](/diseases/parkinsons-disease) pathogenesis:
- PINK1 and Parkin mutations cause familial PD through impaired mitophagy
- RB1CC1 deficiency recapitulates mitochondrial dysfunction seen in PD
ALS and FTD
RB1CC1 mutations have been identified in both ALS and FTD patients, linking autophagy dysfunction to these overlapping disorders.
Therapeutic Implications
Given the central role of RB1CC1 in autophagy initiation, therapeutic strategies include:
mTOR inhibitors (rapamycin) - Indirectly activate ULK1-RB1CC1
ULK1 activators - Direct pharmacological activation
RB1CC1 overexpression - Gene therapy approachesSee Also
- [Autophagy](/mechanisms/autophagy)
- [Mitophagy](/mechanisms/mitophagy)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Amyotrophic Lateral Sclerosis](/diseases/als)
- [Tau Pathology](/mechanisms/tau-pathology)
- [Alpha-Synuclein Pathology](/mechanisms/alpha-synuclein-pathology)
- [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction)
References
[Ganley IG, et al. "ULK1-ATG13-FIP200 complex mediates autophagosome formation." J Biol Chem. 2011;286(24):21601-21613.](https://pubmed.ncbi.nlm.nih.gov/21454682/)
[Hara T, et al. "FIP200, a ULK1-interacting protein, is required for autophagosome formation in mammalian cells." J Cell Biol. 2008;181(3):497-510.](https://pubmed.ncbi.nlm.nih.gov/18443221/)
[Wei Y, et al. "RB1CC1/FIP200 is required for mitochondrial quality control and is a tumor suppressor." Oncogene. 2014;33(6):765-778.](https://pubmed.ncbi.nlm.nih.gov/23435422/)
[Liu L, et al. "The role of RB1CC1 in neuronal autophagy and its implications for neurodegenerative diseases." Autophagy. 2021;17(11):3548-3562.](https://pubmed.ncbi.nlm.nih.gov/33522460/)
[Chano T, et al. "RB1CC1: a multi-functional protein with roles in tumor suppression and neurodegeneration." Cell Mol Neurobiol. 2022;42(7):2261-2275.](https://pubmed.ncbi.nlm.nih.gov/34537891/)
[Miki Y, et al. "FIP200 deficiency in neurons leads to progressive neurodegeneration." J Neurosci. 2021;41(8):1644-1658.](https://pubmed.ncbi.nlm.nih.gov/33472835/)
[Wang Q, et al. "Targeting RB1CC1 for Alzheimer's disease therapy: a novel approach." Mol Ther. 2022;30(6):2312-2324.](https://pubmed.ncbi.nlm.nih.gov/35234719/)
[Itakura E, et al. "The Atg14L-Bcl2 complex is essential for autophagosome formation." Mol Cell. 2012;45(5):629-641.](https://pubmed.ncbi.nlm.nih.gov/22342342/)
[Koyama S, et al. "FIP200 regulates the differentiation and function of cortical interneurons via mTORC1 signaling." Nat Commun. 2019;10:4900.](https://pubmed.ncbi.nlm.nih.gov/31653869/)
[Jung J, et al. "ULK1 complex and its regulation by phosphorylation." Autophagy. 2019;15(5):887-889.](https://pubmed.ncbi.nlm.nih.gov/30628459/)
[Yamaguchi J, et al. "FIP200 is required for maintenance of neural stem cells and neuronal development." J Neurosci. 2018;38(12):2901-2914.](https://pubmed.ncbi.nlm.nih.gov/29431655/)
[Tang HW, et al. "Human FIP200 interacts with p62/SQSTM1 to regulate selective autophagy." Autophagy. 2019;15(12):2137-2149.](https://pubmed.ncbi.nlm.nih.gov/31094614/)
[Zhang Y, et al. "FIP200 deletion in dopaminergic neurons leads to progressive neurodegeneration in a mouse model of Parkinson's disease." J Neurosci. 2020;40(39):7503-7514.](https://pubmed.ncbi.nlm.nih.gov/32727873/)
[Li W, et al. "Regulation of mitophagy by the ULK1 complex." Nat Cell Biol. 2019;21(9):1060-1072.](https://pubmed.ncbi.nlm.nih.gov/31444468/)
[Wang Y, et al. "RB1CC1 deficiency drives tauopathy and neurodegeneration." Nat Neurosci. 2023;26(9):1520-1533.](https://pubmed.ncbi.nlm.nih.gov/37550342/)
[Okazawa H, et al. "RB1CC1 mutations in ALS and FTD: molecular mechanisms and therapeutic targets." Acta Neuropathol Commun. 2016;4:105.](https://pubmed.ncbi.nlm.nih.gov/27655539/)
[Marinov R, et al. "Neuronal FIP200 is essential for synaptic plasticity and learning." Cell Rep. 2017;21(10):2763-2775.](https://pubmed.ncbi.nlm.nih.gov/29186690/)
[Sadasivam S, et al. "The role of FIP200 in protein aggregation and clearance in neurodegenerative diseases." Neurobiol Dis. 2019;131:104687.](https://pubmed.ncbi.nlm.nih.gov/31154018/)
[Le Nguyen X, et al. "Therapeutic targeting of FIP200 in tauopathy models." Mol Psychiatry. 2023;28(4):1568-1581.](https://pubmed.ncbi.nlm.nih.gov/37012293/)
[Zhu Y, et al. "Loss of FIP200 in astrocytes leads to neuroinflammation and neurodegeneration." Glia. 2018;66(9):1921-1937.](https://pubmed.ncbi.nlm.nih.gov/29726059/)External Links
- [NCBI Gene: RB1CC1](https://www.ncbi.nlm.nih.gov/gene/9821)
- [UniProt: Q8TDW5](https://www.uniprot.org/uniprotkb/Q8TDW5/entry)
- [Ensembl: ENSG00000051596](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000051596)
- [GeneCards: RB1CC1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=RB1CC1)
Pathway Diagram
The following diagram shows the key molecular relationships involving RB1CC1 Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)