Interleukin-1 Receptor Accessory Protein

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

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:

Cellular 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

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:

Clinical 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

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