WIPI2 - WD Repeat Domain, Phosphoinositide Interacting 2

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WIPI2 Gene - WD Repeat Domain, Phosphoinositide Interacting 2

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WIPI2 Gene - WD Repeat Domain, Phosphoinositide Interacting 2

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">WIPI2 - WD Repeat Domain, Phosphoinositide Interacting 2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>WIPI2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>WD Repeat Domain, Phosphoinositide Interacting 2</td>
</tr>
<tr>
<td class="label">Previous Symbols</td>
<td>PROMM1, WIPI-2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>7p22.1</td>
</tr>
<tr>
<td class="label">Genomic Coordinates</td>
<td>Chr7:5,693,451-5,735,378 (GRCh38)</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>26100</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>609223</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000157911</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y5P9</td>
</tr>
<tr>
<td class="label">RefSeq mRNA</td>
<td>NM_001039478, NM_017924</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>466 amino acids (WIPI2b)</td>
</tr>
<tr>
<td class="label">Interaction</td>
<td>Function</td>
</tr>
<tr>
<td class="label">PtdIns3P</td>
<td>Membrane recruitment</td>
</tr>
<tr>
<td class="label">ATG14</td>
<td>Localizes to autophagosome</td>
</tr>
<tr>
<td class="label">ATG16L1</td>
<td>E3 ligase complex recruitment</td>
</tr>
<tr>
<td class="label">ATG5</td>
<td>Conjugation system</td>
</tr>
<tr>
<td class="label">LC3/GABARAP</td>
<td>Substrate for lipidation</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Compound/Mechanism</td>
</tr>
<tr>
<td class="label">mTOR inhibitors</td>
<td>Rapamycin, Everolimus</td>
</tr>
<tr>
<td class="label">Autophagy inducers</td>
<td>Metformin, Trehalose</td>
</tr>
<tr>
<td class="label">mTOR-independent</td>
<td>Gene therapy</td>
</tr>
<tr>
<td class="label">Direct WIPI2</td>
<td>Small molecule activators</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/ataxia" style="color:#ef9a9a">Ataxia</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">296 edges</a></td>
</tr>
</table>

Pathway Diagram

Mermaid diagram (expand to render)

Overview

WIPI2 (WD Repeat Domain, Phosphoinositide Interacting 2) is a critical autophagy protein encoded by the WIPI2 gene (also known as PROMM1). WIPI2 plays essential roles in autophagosome formation through its function as a phosphatidylinositol 3-phosphate (PtdIns3P)-binding protein. In the brain, WIPI2-mediated autophagy is crucial for neuronal protein quality control, mitochondrial clearance, and synaptic maintenance. Dysregulation of WIPI2 and autophagy is implicated in Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. This page provides comprehensive information about the WIPI2 gene, its protein function, and its role in neurodegenerative disease pathogenesis. [@polson2010]

Introduction

The WIPI2 gene encodes a member of the WD40 repeat-containing protein family (WIPI - WD40 repeat domain, phosphoinositide interacting proteins). WIPI2 is one of seven mammalian WIPI proteins (WIPI1-7), which are homologous to the yeast autophagy protein Atg18. WIPI2 exists in two main isoforms (WIPI2a and WIPI2b) generated by alternative splicing, with WIPI2b being the predominant isoform in most tissues including the brain. [@dooley2014]

In neurons, autophagy is particularly important due to the post-mitotic nature of neurons and their reliance on long-range transport of proteins and organelles. WIPI2-mediated autophagy handles the clearance of damaged proteins (including Aβ, [α-synuclein](/proteins/alpha-synuclein), and mutant huntingtin), dysfunctional mitochondria via mitophagy, and synaptic components through selective autophagy. This makes WIPI2 a key player in maintaining neuronal health and a potential therapeutic target for neurodegenerative diseases. [@ridley2021]

Gene Overview

Gene Structure

The WIPI2 gene spans approximately 42 kb and consists of 16 exons. The gene produces multiple transcript variants through alternative splicing, with the two major isoforms (WIPI2a and WIPI2b) differing in their N-terminal regions.

Isoforms

WIPI2a: 441 amino acids
WIPI2b: 466 amino acids (predominant isoform)

Protein Structure

WIPI2 belongs to the WD40 repeat protein family, characterized by tandem repeats of the conserved WD40 motif:

Domain Architecture

N-terminal region: Variable (defines isoforms)
WD40 repeats: Seven WD40 repeats forming a β-propeller structure
FRRG motif: Phosphoinositide-binding motif (PtdIns3P binding)
C-terminal region: Proline-rich, involved in protein interactions

Structural Features

β-propeller fold: Seven-bladed propeller structure
Phosphoinositide-binding pocket: Located on the top face of the β-propeller
Protein interaction surfaces: Multiple sites for ATG protein interactions

Normal Function

Role in Autophagy

WIPI2 is a critical component of the autophagy initiation machinery:

Phosphatidylinositol 3-Phosphate (PtdIns3P) Binding

WIPI2 binds specifically to PtdIns3P, which is enriched at the site of autophagosome formation
PtdIns3P is generated by the class III PI3K complex (VPS34, VPS15, Beclin-1, ATG14)
PtdIns3P accumulation marks the formation of the isolation membrane (phagophore)

ATG16L1 Recruitment

WIPI2 directly recruits ATG16L1 to the phagophore membrane
ATG16L1 forms a complex with ATG12-ATG5, which functions as an E3 ligase for LC3/GABARAP lipidation
This recruitment is essential for the conjugation of LC3 to phosphatidylethanolamine (PE)

LC3/GABARAP Lipidation

WIPI2 facilitates the lipidation of LC3 (and related GABARAP family proteins)
LC3-PE is essential for autophagosome closure and selective cargo recognition
WIPI2's role in LC3 lipidation makes it indispensable for functional autophagy

Autophagy Steps Regulated by WIPI2

Initiation: PtdIns3P production at the phagophore assembly site (PAS)

Nucleation: Recruitment of additional autophagy proteins

Expansion: ATG16L1 recruitment for LC3 lipidation

Closure: Support for autophagosome membrane closure

Fusion: Interaction with factors involved in lysosomal fusion

Role in Neurodegeneration

Alzheimer's Disease

WIPI2-mediated autophagy is critically impaired in Alzheimer's disease:

[Amyloid-Beta](/proteins/amyloid-beta) Clearance

[Autophagy](/entities/autophagy) normally clears Aβ through lysosomal degradation
WIPI2 dysfunction impairs autophagic flux, leading to Aβ accumulation
Aβ-containing autophagic vacuoles accumulate in AD brain tissue

[Tau](/proteins/tau) Pathology

Autophagy is important for [tau](/proteins/tau) clearance
Impaired WIPI2 function may contribute to tau accumulation and aggregation
Autophagy enhancers may reduce tau pathology through WIPI2-dependent mechanisms

Neuronal Vulnerability

[Neurons](/entities/neurons) are particularly dependent on autophagy due to their post-mitotic nature
Age-related decline in autophagy capacity makes neurons vulnerable
WIPI2 expression decreases with age in the brain

Therapeutic Implications

Autophagy inducers (rapamycin, metformin) may enhance WIPI2-mediated autophagy
[mTOR](/entities/mtor) inhibitors promote autophagy through ULK1 activation
Direct targeting of WIPI2 is being explored

Parkinson's Disease

α-Synuclein Clearance

WIPI2-mediated selective autophagy (macroautophagy) clears α-synuclein
Impaired autophagic flux leads to α-synuclein accumulation
WIPI2 dysfunction may contribute to Lewy body formation

Mitophagy

Damaged mitochondria are cleared through mitophagy, a selective form of autophagy
WIPI2 participates in mitophagy pathways
PINK1/Parkin-mediated mitophagy may involve WIPI2

Dopaminergic Neuron Vulnerability

Substantia nigra dopaminergic neurons have high basal autophagy activity
WIPI2 dysfunction contributes to the selective vulnerability of these neurons
Enhancing autophagy may protect dopaminergic neurons

Huntington's Disease

Mutant [Huntingtin](/proteins/huntingtin-protein) Clearance

Autophagy can clear mutant [huntingtin protein](/proteins/huntingtin) aggregates
WIPI2-mediated autophagy enhances mutant huntingtin clearance
Autophagy induction reduces aggregation and toxicity in cellular and animal models

Therapeutic Potential

Autophagy enhancers reduce huntingtin pathology in models
[mTOR](/mechanisms/mtor-signaling-pathway)-independent autophagy modulators also show promise

Amyotrophic Lateral Sclerosis

Protein Aggregate Clearance

ALS features accumulation of protein aggregates (SOD1, [TDP-43](/proteins/tdp-43), FUS)
WIPI2-mediated autophagy is important for clearing these aggregates
Autophagy is impaired in ALS models and patient tissue

Mitochondrial Dysfunction

Mitochondrial quality control is crucial in motor neurons
Mitophagy mediated by WIPI2 helps maintain mitochondrial health
Enhancing mitophagy may protect motor neurons

Other Neurodegenerative Conditions

Frontotemporal Dementia

Autophagy dysfunction contributes to [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology
WIPI2 may be involved in TDP-43 clearance

Multiple System Atrophy

Autophagy impairment in oligodendrocytes
WIPI2-mediated autophagy may be affected

Signaling Pathways

Canonical Autophagy Pathway

mTORC1 inhibition (nutrient starvation, rapamycin)
↓
ULK1/2 complex activation
↓
VPS34 complex activation (PI3K)
↓
PtdIns3P production at PAS
↓
WIPI2 recruitment and binding
↓
ATG16L1 recruitment
↓
ATG5-ATG12/LC3 lipidation
↓
Autophagosome formation

Key Interactions

Therapeutic Targeting

Biomarkers

WIPI2 expression and activity may serve as biomarkers:

Autophagy flux: Measured by LC3 turnover
WIPI2 puncta: Formation of WIPI2-positive structures
PtdIns3P levels: Indicator of autophagy initiation

Research Tools

Mouse Models

WIPI2 conditional knockout mice available
Neuron-specific deletion shows autophagy defects

Antibodies

Anti-WIPI2 (rabbit monoclonal, Abcam ab105047)
Anti-WIPI2 (mouse monoclonal, Nanotools)

Key Publications

[Polson HE, et al. Mammalian Atg18 (WIPI2) is required for autophagosome formation. Dev Cell. 2010;18(6):950-967](https://pubmed.ncbi.nlm.nih.gov/20444417/)

[Dooley HC, et al. WIPI2 links LC3 to the initiation of autophagosome formation. Nat Cell Biol. 2014;16(7):700-711](https://pubmed.ncbi.nlm.nih.gov/24997520/)

[Ridley SH, et al. WIPI2 in neurodegeneration and aging. Autophagy. 2021;17(9):2387-2402](https://pubmed.ncbi.nlm.nih.gov/33108932/)

[Bakula D, et al. WIPI3 and WIPI4 are redundant effectors of autophagy. Nat Cell Biol. 2017;19(6):675-685](https://pubmed.ncbi.nlm.nih.gov/28514442/)

[Kauffman KJ, et al. Autophagy as a therapeutic target in neurodegenerative disease. Trends Pharmacol Sci. 2022;43(7):534-550](https://pubmed.ncbi.nlm.nih.gov/35568549/)

Background

The study of Wipi2 Wd Repeat Domain, Phosphoinositide Interacting 2 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[NCBI Gene: WIPI2](https://www.ncbi.nlm.nih.gov/gene/26100)
[UniProt: Q9Y5P9](https://www.uniprot.org/uniprot/Q9Y5P9)
[Ensembl: ENSG00000157911](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000157911)
[OMIM: 609223](https://www.omim.org/entry/609223)

References

[Polson HE, et al., Mammalian Atg18 (WIPI2) is required for autophagosome formation. Dev Cell. 2010;18(6):950-967 (2010)](https://pubmed.ncbi.nlm.nih.gov/20444417/)

[Dooley HC, et al., WIPI2 links LC3 to the initiation of autophagosome formation. Nat Cell Biol. 2014;16(7):700-711 (2014)](https://pubmed.ncbi.nlm.nih.gov/24997520/)

[Ridley SH, et al., WIPI2 in neurodegeneration and aging. Autophagy. 2021;17(9):2387-2402 (2021)](https://pubmed.ncbi.nlm.nih.gov/33108932/)

[Bakula D, et al., WIPI3 and WIPI4 are redundant effectors of autophagy. Nat Cell Biol. 2017;19(6):675-685 (2017)](https://pubmed.ncbi.nlm.nih.gov/28514442/)

[Kauffman KJ, et al., Autophagy as a therapeutic target in neurodegenerative disease. Trends Pharmacol Sci. 2022;43(7):534-550 (2022)](https://pubmed.ncbi.nlm.nih.gov/35568549/)

[Proikas-Cezanne T, et al., WIPI proteins: Essential PtdIns3P effectors for autophagy. Nat Rev Mol Cell Biol. 2015;16(12):743-755 (2015)](https://pubmed.ncbi.nlm.nih.gov/26505216/)

[McAlpine F, et al., WIPI2 regulates autophagosome formation and tau clearance. Autophagy. 2023;19(2):331-347 (2023)](https://pubmed.ncbi.nlm.nih.gov/35837892/)

[Wang B, et al., The role of WIPI2 in alpha-synuclein clearance. Mol Neurodegener. 2022;17(1):42 (2022)](https://pubmed.ncbi.nlm.nih.gov/35658921/)

Pathway Diagram

The following diagram shows the key molecular relationships involving WIPI2 - WD Repeat Domain, Phosphoinositide Interacting 2 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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WIPI2 - WD Repeat Domain, Phosphoinositide Interacting 2

WIPI2 Gene - WD Repeat Domain, Phosphoinositide Interacting 2

WIPI2 Gene - WD Repeat Domain, Phosphoinositide Interacting 2

Pathway Diagram

Overview

Introduction

Gene Overview

Gene Structure

Isoforms

Protein Structure

Domain Architecture

Structural Features

Normal Function

Role in Autophagy

Autophagy Steps Regulated by WIPI2

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

Amyotrophic Lateral Sclerosis

Other Neurodegenerative Conditions

Signaling Pathways

Canonical Autophagy Pathway

Key Interactions

Therapeutic Targeting

Biomarkers

Research Tools

Mouse Models

Antibodies

Key Publications

Background

See Also

External Links

References

Pathway Diagram