| IL1RAP — Interleukin-1 Receptor Accessory Protein | |
|---|---|
| Protein Name | Interleukin-1 Receptor Accessory Protein |
| Gene | IL1RAP |
| UniProt ID | Q9NPH8 |
| PDB IDs | 4DEP, 5BOI, 5BOK |
| Molecular Weight | 65 kDa (567 amino acids) |
| Subcellular Localization | Plasma membrane, Cytoplasm, Endosomes |
| Protein Family | IL-1 receptor family (IL-1R) |
| Brain Expression | Microglia, Astrocytes, Neurons |
IL1RAP (Interleukin-1 Receptor Accessory Protein) is an essential coreceptor for interleukin-1 receptor family members, critical for IL-1 signaling initiation and propagation[1]. It forms heterodimeric complexes with IL-1R1, IL-1R3 (IL1RAP), and IL-1R4 (ST2) to mediate cellular responses to interleukin-1 family cytokines[2]. 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[3]. IL1RAP has emerged as a potential therapeutic target for modulating neuroinflammation in these conditions.
IL1RAP has a distinctive modular structure:
IL1RAP forms signaling complexes with multiple IL-1 receptors:
| Receptor | Coreceptor | Ligand | Signaling Pathway |
|---|---|---|---|
| IL-1R1 | IL1RAP | IL-1β, IL-1α | MyD88, NF-κB |
| IL-1R4 (ST2) | IL1RAP | IL-33 | MyD88, NF-κB |
| IL-1R2 | IL1RAP | IL-1β | Decoy receptor |
| Modification | Site | Functional Effect |
|---|---|---|
| N-glycosylation | Asn66, Asn133, Asn209 | Protein folding, localization |
| Phosphorylation | Tyr513, Tyr536 | Signaling activation |
| Proteolytic cleavage | Arg340 | Receptor shedding |
IL1RAP is essential for IL-1 family cytokine signaling:
In immune cells, IL1RAP-mediated signaling regulates:
IL1RAP plays a significant role in AD pathogenesis through neuroinflammation[4]:
Genetic studies have identified IL1RAP variants associated with increased AD risk, highlighting its importance in disease pathogenesis[5].
In PD, IL1RAP-mediated inflammation affects dopaminergic neurons[6]:
IL1RAP contributes to motor neuron degeneration in ALS[7]:
In HD, IL1RAP affects striatal neuron survival[8]:
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)
IL1RAP is a promising therapeutic target:
| Agent | Target | Phase | Status |
|---|---|---|---|
| Anakinra | IL-1R1 | Phase 2 | Completed |
| Canakinumab | IL-1β | Phase 2 | Ongoing |
| ANX-007 | IL1RAP | Phase 1 | Recruiting |
IL1RAP in cerebrospinal fluid (CSF) may serve as:
Boraschi D et al., IL-1 receptor accessory protein (2018). Cytokine. ↩︎
Sims JE et al., IL-1 receptor family (2010). Nature Reviews Immunology. ↩︎
Heneka MT et al., IL1RAP in neuroinflammation (2020). Nature Reviews Neuroscience. ↩︎
Lombardo DM et al., IL-1β in Alzheimer's disease (2019). Journal of Neurochemistry. ↩︎
Zhao Y et al., IL1RAP variants and AD risk (2021). JAMA Neurology. ↩︎
Kaiser T et al., IL-1 in Parkinson's disease (2019). Neuron. ↩︎
Lee JD et al., IL-1 and ALS (2022). Brain. ↩︎
Valadas JS et al., IL-1 signaling in Huntington's disease (2021). Cerebral Cortex. ↩︎