IRAK3 (IRAK-M): A Key Negative Regulator of Toll-Like Receptor Signaling
Explore IRAK3 gene function, expression, mutations, and its role in immune regulation and disease.
Gene Information Card
| Symbol | IRAK3 |
|---|---|
| Full Name | Interleukin-1 receptor associated kinase 3 |
| Gene Type | protein coding |
| Chromosomal Location | 12q14.3 |
| NCBI Gene ID | 11213 ncbi.nlm.nih.gov/gene/11213 |
| Ensembl ID | ENSG00000190347 |
| UniProt ID | Q9Y616 |
| OMIM ID | 604455 |
| HGNC ID | 6113 |
| Aliases | IRAK-M, IRAKM |
Description
IRAK3 (Interleukin-1 receptor associated kinase 3), also known as IRAK-M, encodes a member of the interleukin-1 receptor-associated kinase family. This protein is a negative regulator of Toll-like receptor (TLR) and IL-1 receptor signaling pathways. It functions by inhibiting the dissociation of IRAK1 and IRAK4 from the receptor complex, thereby suppressing downstream NF-kappaB activation and inflammatory cytokine production. IRAK3 is predominantly expressed in monocytes and macrophages and plays a critical role in endotoxin tolerance and immune homeostasis.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Asthma | IRAK3 expression is altered in airway epithelium; reduced expression may lead to enhanced TLR signaling and chronic inflammation. | ClinVar; PubMed studies |
| Sepsis | Increased IRAK3 expression in monocytes contributes to immunosuppression and endotoxin tolerance in septic patients. | PubMed; UniProt |
| Inflammatory bowel disease (IBD) | Polymorphisms in IRAK3 have been associated with altered inflammatory responses in the gut. | ClinVar; OMIM |
| Cancer (various) | Dysregulated IRAK3 expression can modulate tumor microenvironment and immune evasion. | COSMIC; PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Blood | 12.4 | Medium |
| Spleen | 8.9 | Low |
| Lung | 6.2 | Low |
| Bone Marrow | 5.1 | Low |
| Liver | 1.2 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| THP-1 (monocyte) | 25.3 | High expression; key model for IRAK3 function |
| U937 (monocyte) | 18.7 | High expression |
| HUVEC (endothelial) | 2.1 | Low expression |
| A549 (lung epithelial) | 1.5 | Low expression |
| HeLa (cervical) | 0.8 | Not detected |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs1152912 | SNV (intronic) | ~30% (global) | Associated with altered IRAK3 expression and asthma risk |
| rs1734579 | SNV (intronic) | ~25% | Potential link to sepsis outcomes |
| c.104C>T (p.Thr35Met) | Missense | Rare | Functional impact unknown; reported in ClinVar |
| c.1123A>G (p.Ile375Val) | Missense | Rare | May affect protein stability; not clinically validated |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in IRAK3 are rare; they would lead to enhanced TLR signaling and excessive inflammation, potentially contributing to autoimmune or inflammatory diseases.
Gain of Function (GOF)
Gain-of-function mutations are not well documented; overexpression of IRAK3 is associated with immunosuppression in sepsis and cancer.
Dominant Negative (DN)
Dominant-negative effects have not been clearly established for IRAK3 mutations; however, truncated forms could interfere with signaling complex formation.
View complete mutation data：
Gene Ontology (GO)
| • protein kinase activity | • protein binding |
| • ATP binding | • signal transduction |
| • innate immune response | • negative regulation of NF-kappaB transcription factor activity |
| • toll-like receptor signaling pathway | • inflammatory response |
Pathways
• Toll-like receptor signaling pathway (KEGG: hsa04620)
• IL-1 receptor signaling pathway (Reactome: R-HSA-446652)
• MyD88-dependent cascade (Reactome: R-HSA-166058)
• NF-kappaB signaling (Reactome: R-HSA-975110)
Protein Summary
IRAK3 (IRAK-M) is a 596-amino acid protein with a predicted molecular mass of ~68 kDa. It contains an N-terminal death domain and a central kinase domain, but lacks kinase activity due to critical amino acid substitutions. IRAK3 functions as a negative regulator of TLR/IL-1R signaling by preventing IRAK1/IRAK4 complex dissociation. It is primarily expressed in immune cells, especially monocytes and macrophages. Its expression is induced by TLR stimulation and contributes to endotoxin tolerance. Dysregulation of IRAK3 is implicated in inflammatory diseases and cancer.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| IRAK3 Knockout HEK293 Cell Line | EDJ-KQ7333 | Human | 11213 | Details Get a Quote |
| IRAK3 Knockout HeLa Cell Line | EDJ-KQ32419 | Human | 11213 | Details Get a Quote |
| IRAK3 Knockout A-549 Cell Line | EDJ-KQ64102 | Human | 11213 | Details Get a Quote |
| IRAK3 Knockout HCT 116 Cell Line | EDJ-KQ72550 | Human | 11213 | Details Get a Quote |
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