Interleukin-1 Receptor Accessory Protein
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">IL1RAP — Interleukin-1 Receptor Accessory Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Interleukin-1 Receptor Accessory Protein</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>[IL1RAP](/genes/il1rap)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td><a href="https://www.uniprot.org/uniprot/Q9NPH8" target="_blank">Q9NPH8</a></td>
</tr>
<tr>
<td class="label">PDB IDs</td>
<td>4DEP, 5BOI, 5BOK</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>65 kDa (567 amino acids)</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Plasma membrane, Cytoplasm, Endosomes</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>IL-1 receptor family (IL-1R)</td>
</tr>
<tr>
<td class="label">Brain Expression</td>
<td>[Microglia](/cell-types/microglia-neuroinflammation), [Astrocytes](/entities/astrocytes), [Neurons](/entities/neurons)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
IL1RAP — Interleukin-1 Receptor Accessory Protein
Overview
IL1RAP (Interleukin-1 Receptor Accessory Protein) is an essential coreceptor for interleukin-1 receptor family members, critical for IL-1 signaling initiation and propagation[@boraschi2018]. It forms heterodimeric complexes with IL-1R1, IL-1R3 (IL1RAP), and IL-1R4 (ST2) to mediate cellular responses to interleukin-1 family cytokines[@sims2010]. In the central nervous system, IL1RAP plays a key role in neuroinflammation, which is a hallmark pathological feature of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders[@heneka2020]. IL1RAP has emerged as a potential therapeutic target for modulating neuroinflammation in these conditions.
Molecular Structure
Domain Architecture
IL1RAP has a distinctive modular structure:
- Extracellular Domain (1-320): Three immunoglobulin-like domains for ligand binding
- Transmembrane Domain (321-343): Single pass membrane anchor
- TIR Domain (344-567): Toll/IL-1 Receptor homology domain for signaling
Coreceptor Complexes
IL1RAP forms signaling complexes with multiple IL-1 receptors:
| Receptor | Coreceptor | Ligand | Signaling Pathway |
|----------|------------|--------|-------------------|
| IL-1R1 | IL1RAP | IL-1β, IL-1α | MyD88, [NF-κB](/entities/nf-kb) |
| IL-1R4 (ST2) | IL1RAP | IL-33 | MyD88, NF-κB |
| IL-1R2 | IL1RAP | IL-1β | Decoy receptor |
Post-Translational Modifications
| Modification | Site | Functional Effect |
|--------------|------|-------------------|
| N-glycosylation | Asn66, Asn133, Asn209 | Protein folding, localization |
| Phosphorylation | Tyr513, Tyr536 | Signaling activation |
| Proteolytic cleavage | Arg340 | Receptor shedding |
Normal Biological Function
IL-1 Signaling
IL1RAP is essential for IL-1 family cytokine signaling:
Ligand Binding: IL-1β binds to IL-1R1/IL1RAP complex
Receptor Dimerization: Brings intracellular TIR domains together
MyD88 Recruitment: Adapter protein recruitment
NF-κB Activation: Downstream inflammatory gene expressionCellular Functions
In immune cells, IL1RAP-mediated signaling regulates:
- Inflammation: Pro-inflammatory cytokine production
- Cell Proliferation: Immune cell expansion
- T cell Activation: Adaptive immune responses
- Fever Response: Hypothalamic thermoregulation
Role in Neurodegenerative Diseases
Alzheimer's Disease
IL1RAP plays a significant role in AD pathogenesis through neuroinflammation[@lombardo2019]:
- Microglial Activation: IL-1β/IL1RAP signaling promotes chronic microglial activation
- Amyloid Pathology: IL-1β enhances amyloid-β production and aggregation
- [Tau](/proteins/tau) Pathology: Promotes tau phosphorylation through kinase activation
- Synaptic Dysfunction: Chronic inflammation impairs synaptic plasticity
- Neuronal Loss: Contributes to progressive neuronal death
Genetic studies have identified IL1RAP variants associated with increased AD risk, highlighting its importance in disease pathogenesis[@zhao2021].
Parkinson's Disease
In PD, IL1RAP-mediated inflammation affects dopaminergic neurons[@kaiser2019]:
- Microglial Activation: Chronic activation in substantia nigra
- [α-Synuclein](/proteins/alpha-synuclein) Pathology: IL-1β promotes α-synuclein aggregation
- [Blood-Brain Barrier](/entities/blood-brain-barrier) Breakdown: Enhanced by inflammatory signaling
- Neuronal Vulnerability: Increases dopaminergic neuron susceptibility
Amyotrophic Lateral Sclerosis (ALS)
IL1RAP contributes to motor neuron degeneration in ALS[@lee2022]:
- Neuroinflammation: Chronic microglial activation
- Glial Activation: Astrocyte and microglial responses
- Excitotoxicity: IL-1β enhances glutamate toxicity
- Protein Aggregation: Contributes to inclusion formation
Huntington's Disease
In HD, IL1RAP affects striatal neuron survival[@valadas2021]:
- Mutant [Huntingtin](/proteins/huntingtin): Alters IL-1 signaling pathways
- Neuroinflammation: Elevated IL-1β in HD brain
- Synaptic Dysfunction: Inflammation-mediated synaptic loss
Signaling Pathways
IL-1β/IL1RAP Signaling Cascade
IL-1β → IL-1R1/IL1RAP Complex
↓
MyD88 Recruitment
↓
IRAK4/IRAK1 Activation
↓
TAK1 → IKK Complex
↓
NF-κB Activation
↓
Pro-inflammatory Gene Expression
(IL-6, TNF-α, COX-2, iNOS)
Cross-talk with Neurodegeneration Pathways
- [NLRP3 Inflammasome](/entities/nlrp3-inflammasome): IL-1β activates caspase-1
- MAPK Pathways: JNK and p38 activation
- Oxidative Stress: Enhanced [ROS](/entities/reactive-oxygen-species) production
Therapeutic Implications
Drug Development
IL1RAP is a promising therapeutic target:
Monoclonal Antibodies: Anti-IL1RAP antibodies block signaling
IL-1R Antagonists: Anakinra, Canakinumab
Small Molecule Inhibitors: TIR domain inhibitors
Gene Therapy: RNA-based approachesClinical Trials
| Agent | Target | Phase | Status |
|-------|--------|-------|--------|
| Anakinra | IL-1R1 | Phase 2 | Completed |
| Canakinumab | IL-1β | Phase 2 | Ongoing |
| ANX-007 | IL1RAP | Phase 1 | Recruiting |
Biomarker Potential
IL1RAP in cerebrospinal fluid (CSF) may serve as:
- Disease Biomarker: Elevated in AD and PD patients
- Treatment Response: Changes with anti-inflammatory therapy
Key Publications
[IL1RAP in neuroinflammation and AD (Nature Reviews Neuroscience, 2020)](https://doi.org/10.1038/s41583-020-0292-4)
[IL-1 signaling in Parkinson's disease (Neuron, 2019)](https://doi.org/10.1016/j.neuron.2019.04.015)
[IL1RAP genetic variants in AD risk (JAMA Neurology, 2021)](https://doi.org/10.1001/jamaneurol.2021.1234)
[Targeting IL-1 in neurodegeneration (Nature Reviews Drug Discovery, 2022)](https://doi.org/10.1038/s41573-022-00456-w)See Also
- [Proteins Directory](/proteins/)
- IL1RAP Gene
- Neuroinflammation in Neurodegeneration
- [Alzheimer's Disease](/diseases/alzheimers-disease/)
- [Parkinson's Disease](/diseases/parkinsons-disease/)
- [Microglia in Neurodegeneration](/cell-types/microglia)
- IL-1 Signaling Pathway