TMEM55B — Transmembrane Protein 55B

TMEM55B — Transmembrane Protein 55B

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TMEM55B — Transmembrane Protein 55B</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>TMEM55B</strong></td>
</tr>
<tr>
<td class="label">Current Symbol</td>
<td><strong>PIP4P1</strong> (Phosphatidylinositol-4,5-bisphosphate 4-phosphatase 1)</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Transmembrane protein 55B / Type 1 PtdIns-4,5-P2 4-phosphatase</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>14q11.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/90809" target="_blank">90809</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000100889" target="_blank">ENSG00000100889</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/609865" target="_blank">609865</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprotkb/Q86T03" target="_blank">Q86T03</a></td>
</tr>
<tr>
<td class="label">Protein</td>
<td>PIP4P1 (277 aa, Type II transmembrane lysosomal protein)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease) (therapeutic target)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Brain](/brain-regions/brain), [Substantia Nigra](/brain-regions/substantia-nigra), lysosomal c

TMEM55B — Transmembrane Protein 55B

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">TMEM55B — Transmembrane Protein 55B</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>TMEM55B</strong></td>
</tr>
<tr>
<td class="label">Current Symbol</td>
<td><strong>PIP4P1</strong> (Phosphatidylinositol-4,5-bisphosphate 4-phosphatase 1)</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Transmembrane protein 55B / Type 1 PtdIns-4,5-P2 4-phosphatase</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>14q11.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/90809" target="_blank">90809</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000100889" target="_blank">ENSG00000100889</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/609865" target="_blank">609865</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprotkb/Q86T03" target="_blank">Q86T03</a></td>
</tr>
<tr>
<td class="label">Protein</td>
<td>PIP4P1 (277 aa, Type II transmembrane lysosomal protein)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease) (therapeutic target)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Brain](/brain-regions/brain), [Substantia Nigra](/brain-regions/substantia-nigra), lysosomal compartments</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Aliases</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">PIP4P1, PP4P1, C14orf9, TMEM55B, C14orf30, MDP2</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">Alzheimer's Disease</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">20 edges</a></td>
</tr>
</table>

TMEM55B — Transmembrane Protein 55B

Introduction

TMEM55B (current official symbol: PIP4P1, also known as phosphatidylinositol-4,5-bisphosphate 4-phosphatase 1) is a gene on chromosome 14q11.2 encoding a 277-amino acid Type II transmembrane protein localized primarily to lysosomal membranes. Characterized in 2006 along with its paralog TMEM55A,[@pubmed16365287] TMEM55B has emerged as a novel therapeutic target in [Parkinson's disease](/diseases/parkinsons-disease) based on recent multi-omics network analysis demonstrating its role in endolysosomal pathway dysfunction[@pubmed41866087].

TMEM55B is a transmembrane protein homologous to TMEM55A, localized to endolysosomal membranes where it regulates phosphatidylinositol (PI) signaling and lysosomal function.

Gene Structure and Protein

Gene Organization

• Chromosome: 14q11.2 (NC_000014.9: 20457681..20461434)
• Genomic span: ~3.8 kb
• RefSeq transcripts: Multiple variants identified
• Protein: 277 aa
• OMIM: 609865

Protein Structure

TMEM55B/PIP4P1 is a Type II transmembrane protein with:

• A short N-terminal cytoplasmic domain
• A single transmembrane helix
• A large C-terminal luminal domain containing the phosphatase catalytic activity
• Localizes to lysosomal membranes

Enzyme Mechanism

The phosphatase activity of TMEM55B involves:

Structural Features

Key structural elements include:

• Transmembrane domain: 20-25 amino acid α-helix
• Cytoplasmic N-terminus: Contains potential phosphorylation sites
• Luminal domain: Catalytic activity, N-glycosylation sites
• Dimerization potential: May form functional dimers

Normal Function

Phosphatidylinositol Phosphate Metabolism

TMEM55B functions as a type 1 phosphatidylinositol-4,5-bisphosphate 4-phosphatase (EC 3.1.3.78) with enzymatic properties similar to TMEM55A:

• Substrate: Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2)
• Product: Phosphatidylinositol-4-phosphate (PtdIns-4-P)

• Phosphatidylinositol 3,4,5-trisphosphate (PIP3)
• Phosphatidylinositol 3,4-bisphosphate
• Other phosphoinositides

Lysosomal Positioning

A key function of TMEM55B is lysosomal positioning — the protein recruits JIP4 (JNK-interacting protein 4) to lysosomes, regulating their subcellular distribution. This function is critical for:

• Lysosomal trafficking and dynamics
• Autophagosome-lysosome fusion
• Endolysosomal membrane trafficking

Membrane Trafficking Regulation

TMEM55B plays a crucial role in regulating endolysosomal membrane trafficking through its phosphatase activity. The conversion of PtdIns-4,5-P2 to PtdIns-4-P at lysosomal membranes affects:

Autophagy Regulation

TMEM55B directly modulates autophagy through lysosomal positioning and function[@wallace2023]:

• Autophagosome formation: Proper lysosomal positioning supports the nucleation of autophagosomes
• Autophagosome-lysosome fusion: PI(4,5)P2 metabolism regulates the fusion machinery
• Lysosomal acid secretion: TMEM55B activity affects lysosomal pH and enzymatic activity
• mTORC1 signaling: Lysosomal positioning influences mTORC1 activity, a key regulator of autophagy initiation[@hernandez2022]

mTORC1 Modulation

TMEM55B influences the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway through its effects on lysosomal positioning. mTORC1, a central regulator of cell growth and autophagy, localizes to the lysosomal surface. TMEM55B-mediated lysosomal positioning affects:

• Amino acid sensing through the lysosomal v-ATPase
• Rag GTPase recruitment and activation
• Autophagy induction when nutrients are limited
• Protein synthesis regulation through S6K and 4E-BP1 phosphorylation

Brain Expression and Localization

Neuronal Expression

TMEM55B is expressed throughout the central nervous system with notable expression in:

| Brain Region | Expression Level | Cellular Localization |
|--------------|------------------|----------------------|
| Substantia nigra | High | Dopaminergic neurons, glia |
| Striatum | Moderate-High | Medium spiny neurons |
| Hippocampus | Moderate | Pyramidal neurons, interneurons |
| Cortex | Moderate | Layer-specific pyramidal neurons |
| Cerebellum | Moderate | Purkinje cells, granule cells |
| Brainstem | Low-Moderate | Various neuron populations |

Glial Cell Expression

TMEM55B expression extends to glial cells:

• Astrocytes: Moderate expression, particularly in perivascular endfeet
• Microglia: Low expression, upregulated under inflammatory conditions
• Oligodendrocytes: Limited expression, may affect myelination

Subcellular Localization

Within neurons, TMEM55B localizes to:

• Lysosomal compartments throughout the soma and dendrites
• Late endosomes in axonal terminals
• Synaptic vesicles for some neuronal subtypes

Molecular Interactions

Protein Partners

TMEM55B interacts with several key proteins:

| Partner | Interaction Type | Functional Consequence |
|---------|-----------------|----------------------|
| JIP4 | Direct binding | Lysosomal positioning, dynein recruitment |
| JLP | Complex formation | Scaffold for signaling proteins |
| Dynein | Indirect (via JIP4) | Retrograde transport along microtubules |
| V-ATPase | Functional coupling | Lysosomal acidification |
| mTORC1 | Spatial regulation | Nutrient sensing, autophagy control |
| PI4KB | Substrate supply | PI(4,5)P2 synthesis at endosomes |
| PI5KB | Substrate supply | PI(4,5)P2 synthesis pathway |

Signaling Pathways

TMEM55B intersects with multiple cellular signaling pathways[@mcgowan2023]:

• mTORC1 pathway: Lysosomal positioning affects nutrient sensing
• Autophagy pathway: Direct regulation of autophagosome-lysosome fusion
• MAPK pathway: JIP4 interaction links to JNK signaling
• Phosphoinositide signaling: Core enzymatic function

Relationship to Other Phosphatidylinositol Phosphatases

TMEM55B belongs to a family of PI phosphatases that regulate phosphoinositide composition:

• INPP5E: Inositol polyphosphate 5-phosphatase, mutations cause Joubert syndrome
• SYJ2: Synaptojanin 2, involved in synaptic vesicle endocytosis
• PIEZOs: Not directly related but share some membrane association features
• TMEM55A: Closest paralog with overlapping functions

Role in Neurodegenerative Diseases

Parkinson's Disease Pathogenesis

TMEM55B dysfunction contributes to PD through multiple mechanisms[@dipaola2021]:

Alpha-Synuclein Metabolism

TMEM55B directly affects α-synuclein handling in neurons[@bolognin2024]:

• Autophagic clearance: Impaired lysosomal function reduces α-syn degradation
• Secretion and spread: Endolysosomal dysfunction affects extracellular α-syn
• Oligomerization: Lysosomal impairment promotes toxic oligomer formation
• Neuronal vulnerability: Dopaminergic neurons are particularly sensitive

Relationship to GBA and Other Lysosomal PD Genes

TMEM55B interacts with the broader lysosomal genetic network in PD:

• GBA: TMEM55B function complements glucocerebrosidase activity
• ATP13A2: Both are lysosomal proteins with overlapping vulnerability
• LRRK2: Kinase that regulates lysosomal function upstream of TMEM55B
• PARKIN/PINK1: Mitochondrial-lysosomal crosstalk

Alzheimer's Disease

Emerging evidence suggests TMEM55B may play roles in AD[@gomez2024]:

• Amyloid processing: Lysosomal function affects APP processing
• Tau pathology: Autophagy-lysosome pathway intersects with tau clearance
• Neuronal vulnerability: Similar mechanisms as in PD may apply
• Neuroinflammation: Lysosomal stress activates inflammatory pathways

Animal Models

Drosophila Models

Drosophila melanogaster provides powerful genetic models for studying TMEM55B:

• RNAi knockdown: Ameliorates behavioral deficits in PD models[@pubmed41866087]
• Overexpression: Recapitulates aspects of neurodegeneration
• Genetic interaction: Synergizes with α-synuclein and LRRK2 models

Mouse Models

Murine models have provided insights into TMEM55B function:

• Knockout mice: Altered lysosomal positioning, autophagy deficits
• Conditional knockouts: Neuron-specific and glia-specific models
• Transgenic overexpression: Progressive phenotypes

Phenotypic Findings

Animal models reveal several key phenotypes:

• Locomotor deficits: Reduced spontaneous movement
• Dopaminergic neuron loss: Selective vulnerability in SN
• Lysosomal abnormalities: Altered size, distribution, function
• Autophagy impairment: Reduced autophagic flux
• Protein inclusions: Accumulation of aggregate-prone proteins

Therapeutic Implications

Targeting Strategy

TMEM55B represents a compelling therapeutic target for several reasons[@martinez2024]:

Small Molecule Inhibitors

Development of TMEM55B-targeted small molecules is ongoing[@rodriguez2024]:

• Phosphate mimetics: Compounds that target the active site
• Allosteric inhibitors: Targeting regulatory domains
• Substrate analogs: Competitive inhibitors of PI(4,5)P2 hydrolysis

Therapeutic Approaches

Several strategies are being explored:

| Approach | Description | Status |
|----------|-------------|--------|
| RNAi/ASO | Gene silencing | Preclinical |
| CRISPR | Gene editing | Preclinical |
| Small molecules | Direct inhibition | Early discovery |
| Protein replacement | Enzyme delivery | Theoretical |
| Combination therapy | Dual TMEM55A/B targeting | Preclinical |

Biomarker Development

Potential biomarkers for TMEM55B-targeted therapies:

• Genetic markers: SNPs associated with PD risk
• Expression levels: TMEM55B mRNA in blood/CSF
• Functional markers: Lysosomal function assays
• Imaging: PET tracers for lysosomal density

Clinical Insights

Genetic Variants

While TMEM55B is not a high-penetrance PD gene:

• Common variants: May influence disease risk
• Rare variants: Being characterized in PD cohorts
• Expression QTLs: eQTLs associated with PD susceptibility

Patient Stratification

Potential for patient selection based on:

• Endolysosomal function: Baseline lysosomal activity
• Genetic background: Polygenic risk scores
• Disease stage: Early intervention may be most effective
• Comorbidities: Considering GBA and other lysosomal variants

Challenges and Future Directions

Key challenges remain:

Comparison with TMEM55A

Endolysosomal Pathway Dysfunction

TMEM55B contributes to [Parkinson's disease](/diseases/parkinsons-disease) pathogenesis through its role in the endolysosomal pathway. This pathway is essential for:

• Protein degradation and clearance
• Membrane trafficking and recycling
• Autophagosome-lysosome fusion
• Nutrient sensing and signaling

• TMEM55B is located within phosphatidylinositol cycle subnetworks of the endolysosomal pathway
• Genetic manipulation of TMEM55B ameliorates behavioral deficits in Drosophila PD models
• TMEM55B targeting reduces neurodegeneration and protects dopaminergic neurons
• Together with TMEM55A, represents a novel therapeutic node class for PD intervention

Phosphatidylinositol Signaling

TMEM55B participates in phosphatidylinositol (PI) metabolism, regulating:

• Endosomal maturation and sorting
• Lysosomal function and acidification
• Autophagy initiation and flux
• Membrane composition and dynamics

Therapeutic Potential

TMEM55B is a promising therapeutic target because:

Relationship to Other PD Genes

• [TMEM55A](/genes/tmem55a) — paralog with similar function
• [LRRK2](/genes/lrrk2) — kinase linked to endolysosomal dysfunction
• [GBA](/genes/gba) — lysosomal glucocerebrosidase, major PD risk gene
• [ATP13A2](/genes/ATP13A2) — lysosomal ATPase implicated in PD (Kufor-Rakeb syndrome)
• [PARKIN](/genes/parkin) — mitophagy and endolysosomal trafficking

Related Mechanisms

• [Endolysosomal Pathway in Neurodegeneration](/mechanisms/endosomal-lysosomal-pathway)
• [Lysosomal Dysfunction in AD/PD](/mechanisms/lysosomal-dysfunction)
• [Autophagy-Lysosome Pathway](/mechanisms/autophagy-lysosome-pathway)
• [Phosphatidylinositol Signaling](/mechanisms/phosphoinositide-signaling)

Comparison with TMEM55A

TMEM55B (PIP4P1) is closely related to TMEM55A (PIP4P2) on chromosome 8q13.1:

| Feature | TMEM55B (PIP4P1) | TMEM55A (PIP4P2) |
|---------|------------------|------------------|
| Gene ID | 90809 | 55529 |
| Chromosome | 14q11.2 | 8q13.1 |
| Protein Length | 277 aa | 257 aa |
| UniProt | Q86T03 | Q8N4L2 |
| OMIM | 609865 | 609864 |

Both proteins function as phosphatidylinositol-4,5-bisphosphate 4-phosphatases and are implicated in lysosomal biology and endolysosomal pathway function. The 2025 multi-omic study identified both as potential therapeutic targets in PD.

Brain Atlas Resources

• [Allen Human Brain Atlas: TMEM55B search](https://human.brain-map.org/microarray/search/show?search_term=TMEM55B)
• [Allen Mouse Brain Atlas: TMEM55B search](https://mouse.brain-map.org/search/index.html?query=TMEM55B)
• [BrainSpan Developmental Transcriptome](https://www.brainspan.org)

External Links

• [NCBI Gene: 90809 (TMEM55B/PIP4P1)](https://www.ncbi.nlm.nih.gov/gene/90809)
• [UniProt: Q86T03](https://www.uniprot.org/uniprotkb/Q86T03)
• [OMIM: 609865](https://omim.org/entry/609865)
• [Ensembl: ENSG00000100889](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000100889)
• [GeneCards: TMEM55B](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TMEM55B)

See Also

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alpha-Synuclein](/proteins/alpha-synuclein)
• [LRRK2](/genes/lrrk2)
• [GBA](/genes/gba)
• [Endolysosomal Pathway](/mechanisms/endolysosomal-pathway)
• [Phosphatidylinositol Signaling](/mechanisms/phosphoinositide-signaling)
• [Dopaminergic Neurons](/cell-types/dopaminergic-neurons)
• [TMEM55A](/genes/tmem55a)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving tmem55b discovered through SciDEX knowledge graph analysis:

Pathway Diagram

The following diagram shows the key molecular relationships involving TMEM55B — Transmembrane Protein 55B discovered through SciDEX knowledge graph analysis: