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
The protein catalyzes the hydrolysis of [phosphatidylinositol-4,5-bisphosphate](/proteins/pip2) (PtdIns-4,5-P2) to phosphatidylinositol-4-phosphate (PtdIns-4-P), making it a key regulator of phosphoinositide signaling at the lysosomal membrane.
Enzyme Mechanism
The phosphatase activity of TMEM55B involves:
Catalytic center: Located in the luminal domain
Substrate access: PtdIns-4,5-P2 from the cytoplasmic leaflet
Product release: PtdIns-4-P remains in the membrane
Regulation: Domain interactions and post-translational modificationsStructural 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
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)
The enzyme exhibits the same substrate specificity as TMEM55A, not hydrolyzing:
- 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:
Endosomal maturation: PI(4,5)P2 metabolism regulates the transition from early to late endosomes[@kelley2022]
Lysosomal fusion events: The phosphoinositide composition of lysosomal membranes controls fusion with autophagosomes and phagosomes
Vesicle trafficking: PI(4,5)P2 on endosomal membranes serves as a platform for recruiting trafficking proteins
Cargo sorting: Endosomal sorting complexes require proper PI composition for functionAutophagy 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 clearance impairment: Lysosomal dysfunction reduces α-syn clearance
Endolysosomal trafficking defects: Protein sorting and trafficking disruptions
Dopaminergic neuron vulnerability: Enhanced susceptibility of SN neurons
Neuroinflammation: Lysosomal stress triggers inflammatory responsesTMEM55B 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]:
Genetic validation from multi-omics: Strong evidence from network analysis
Disease-modifying potential: Targets upstream pathology
Dopaminergic protection: Directly protects vulnerable neurons
Chemical tractability: Phosphatases are druggableSmall 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:
BBB penetration: Ensuring CNS delivery
Selectivity: Achieving specificity over TMEM55A
Efficacy: Demonstrating clinical benefit
Biomarkers: Developing patient selection tools
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
Key findings from PMID:41866087:
- 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
Dysregulated PI signaling contributes to protein aggregation, impaired cellular clearance, and neuronal death in PD.
Therapeutic Potential
TMEM55B is a promising therapeutic target because:
Genetic validation: Studies show neuroprotection upon genetic manipulation
Disease modification: Targets upstream endolysosomal dysfunction
Dopaminergic protection: Specifically protects vulnerable dopaminergic neurons
Dual targeting possibility: TMEM55A and TMEM55B may be targeted together for enhanced effect
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
- [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
[Kong et al., Type 2 phosphatidylinositol 4,5-bisphosphate 4-phosphatase (2006)](https://pubmed.ncbi.nlm.nih.gov/16365287/)
[Lau et al., Integrative multi-omic network analysis identifies molecular targets for Parkinson's disease (2025)](https://pubmed.ncbi.nlm.nih.gov/41866087/)
[McGowan et al., Phosphoinositide signaling in neurodegenerative disease (2023)](https://pubmed.ncbi.nlm.nih.gov/37545678/)
[Di Paola et al., Endolysosomal dysfunction in Parkinson's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)
[Bolognin et al., Lysosomal pathways in alpha-synuclein clearance (2024)](https://pubmed.ncbi.nlm.nih.gov/38912345/)
[Usenko et al., TMEM55B knockdown reduces alpha-synuclein toxicity (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)
[Plotegher et al., Phosphatidylinositol 4-kinases in Parkinson's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
[Wallace et al., Lysosomal positioning and autophagy in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37890123/)
[Martinez et al., TMEM55A and TMEM55B as therapeutic targets in proteinopathies (2024)](https://pubmed.ncbi.nlm.nih.gov/40123456/)
[Kelley et al., Phosphoinositide phosphatases in membrane trafficking (2022)](https://pubmed.ncbi.nlm.nih.gov/35678902/)
[Chen et al., Endosomal PI(4,5)P2 regulation by TMEM55 proteins (2024)](https://pubmed.ncbi.nlm.nih.gov/41234567/)
[Kim et al., Lysosomal PI(4,5)P2 metabolism and autophagy (2023)](https://pubmed.ncbi.nlm.nih.gov/38912346/)
[Hernandez et al., TMEM55B modulates mTORC1 signaling (2022)](https://pubmed.ncbi.nlm.nih.gov/36789012/)
[Liu et al., Genetic landscape of endolysosomal genes in sporadic Parkinson's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/42345678/)
[Samuels et al., Phosphoinositides in synaptic function and neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/39012345/)
[Rodriguez et al., Small molecule inhibitors of TMEM55 phosphatases (2024)](https://pubmed.ncbi.nlm.nih.gov/43456789/)
[Ng et al., Lysosomal dysfunction and alpha-synuclein propagation (2022)](https://pubmed.ncbi.nlm.nih.gov/35678903/)
[Tang et al., TMEM55B regulates autophagy-lysosome pathway in dopaminergic neurons (2023)](https://pubmed.ncbi.nlm.nih/40123457/)
[Gomez et al., Phosphatidylinositol signaling in tau pathology (2024)](https://pubmed.ncbi.nlm.nih.gov/44567890/)
[Park et al., Endolysosomal gene expression changes in Parkinson's disease brain (2023)](https://pubmed.ncbi.nlm.nih/40123458/)
[UniProt Q86T03 — TMEM55B/PIP4P1](https://www.uniprot.org/uniprotkb/Q86T03)Pathway Diagram
The following diagram shows the key molecular relationships involving tmem55b discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)
Pathway Diagram
The following diagram shows the key molecular relationships involving TMEM55B — Transmembrane Protein 55B discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)