HGNC Approved Gene Symbol: IRAK2
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38): 3:10,164,919-10,243,745 (from NCBI)
The interleukin-1 receptor (IL1R) signaling pathway leads to nuclear factor kappa-B (NFKB; e.g., 164011) activation in mammals. After binding to IL1 (e.g., 147760), the type 1 IL1R (IL1R1; 147810) associates with the IL1R accessory protein (IL1RAP; 602626) and initiates the signaling cascade. Multiple protein kinase activities coprecipitate with IL1R1, including IRAK1 (300283). By searching EST databases for sequences similar to IRAK1, Muzio et al. (1997) identified IRAK2. The deduced protein contains 590 amino acids. Northern blot analysis detected an approximately 4-kb IRAK2 transcript in a variety of adult human tissues.
Crystal Structure
Lin et al. (2010) reported the crystal structure of the MyD88 (602170)-IRAK4 (606883)-IRAK2 death domain complex, which revealed a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4, and 4 IRAK2 death domains. Assembly of this helical signaling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88-IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual death domains in the complex, which are confirmed by mutagenesis and previously identified signaling mutations. Specificities of myddosome formation are dictated by both molecular complementation and correspondence of surface electrostatics.
Muzio et al. (1997) showed that ectopic expression of IRAK2 protein induced NFKB activation, whereas expression of truncated IRAK2 proteins did not. Truncated forms of IRAK2 acted as dominant-negative inhibitors of IL1R-induced NFKB activity. IRAK2 coprecipitated with MYD88 (602170) and TRAF6 (602355), another protein implicated in the IL1 signaling pathway and shown to complex with IRAK1. Muzio et al. (1997) concluded that IRAK2 is a proximal mediator of IL1, is a component of the IL1R signaling complex, and is required for IL1R-induced NFKB activation.
Conner et al. (2009) detected an earlier, more potent Toll-like receptor (TLR; see 603030)-mediated induction of Il6 (147620) transcription in a wild-derived mouse strain, MOLF/Ei, compared with the classical inbred strain C57BL/6J. The phenotype correlated with increased activity of the I-kappa-B kinase (see 600664) axis and p38 (MAPK14; 600289), but not Mapk1 (176948), Mapk3 (601795), or Mapk8 (601158). The trait was mapped to the Why1 locus, which contains Irak2, on mouse chromosome 6. Conner et al. (2009) showed that, in the MOLF/Ei TLR signaling network, Irak2 promoted early NF-kappa-B activity and was essential for p38 activation. In the MOLF/Ei strain, they identified a 10-bp deletion in the promoter region of an inhibitory Irak2 variant, Irak2c, leading to an increased ratio of pro- to antiinflammatory Irak2 isoforms. Conner et al. (2009) concluded that Irak2 is an essential component of the early TLR response in wild-derived MOLF/Ei mice and that the pathway of p38 and NF-kappa-B activation is distinct in this organism.
Conner, J. R., Smirnova, I. I., Poltorak, A. A mutation in Irak2c identifies IRAK-2 as a central component of the TLR regulatory network of wild-derived mice. J. Exp. Med. 206: 1615-1631, 2009. [PubMed: 19564352] [Full Text: https://doi.org/10.1084/jem.20090490]
Lin, S.-C., Lo, Y.-C., Wu, H. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465: 885-890, 2010. [PubMed: 20485341] [Full Text: https://doi.org/10.1038/nature09121]
Muzio, M., Ni, J., Feng, P., Dixit, V. M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278: 1612-1615, 1997. [PubMed: 9374458] [Full Text: https://doi.org/10.1126/science.278.5343.1612]