Toll-like receptor signaling: IRAK2 stays the course
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The interleukin-1 receptor-associated kinase 2 (IRAK2) is dispensable in the early phase of Toll-like receptor signaling but is required for sustained NF-κB activity.
Toll-like receptors (TLRs) are an integral part of the innate immune defense system. TLRs recognize microbial components and associate with adaptor proteins that recruit interleukin-1 receptor-associated kinases (IRAK1, IRAK2, IRAK-M and IRAK4). IRAKs stimulate cytoplasmic signaling cascades to affect NF-κB-mediated transcription of inflammatory cytokines, including interleukin-6 (Il6) and tumor necrosis factor (Tnfa). Overexpression of IRAK2 activates NF-κB, but its precise function in the innate immune response is unknown. In Nature Immunology, Shizuo Akira and colleagues now reveal that the activity of IRAK2 is dependent on an intact kinase domain, and show that IRAK1 and IRAK2 have sequential roles in transducing TLR signaling.
Irak2 knockout mice were generated to assess the role of IRAK2 in TLR signaling. Macrophages from Irak2-/- mice showed impaired Il6 expression following TLR2 stimulation. Tnfa and cyclooxygenase-2 (Cox2) were induced normally, but their expression unexpectedly declined four hours after TLR2 stimulation. Similarly, NF-κB DNA binding was not sustained beyond four hours after TLR2 stimulation, suggesting that IRAK2 is required for prolonged NF-κB activity.
IRAK1 and IRAK4 both possess intrinsic kinase activity, but whether IRAK2 is catalytically active is unclear. Exogenous expression of kinase-defective IRAK2 in Irak2-/- macrophages could not rescue IL-6 or TNF-α expression, whereas expression of wild-type IRAK2 permitted normal cytokine induction following TLR2 activation. Furthermore, wild-type, but not kinase-deficient IRAK2 was phosphorylated in vitro. Therefore, an intact kinase domain is required for IRAK2 phosphorylation and function.
Similar to Irak1-/- mice, IRAK2-deficient mice were able to mount an impaired response to infection, suggesting functional redundancy with another IRAK family member. TLR2 stimulation induced rapid but transient activation of IRAK1. In contrast, phosphorylation and activation of IRAK2 began 30 minutes after TLR2 stimulation and was sustained for up to eight hours. Microarray analysis showed that wild-type and IRAK2-deficient macrophages expressed a similar cluster of TLR2-inducible genes two hours after TLR2 activation, but expression of TLR2-inducible genes was significantly reduced in Irak2-/- macrophages after eight hours. Macrophages from Irak1/Irak2 double-knockout mice showed severe deficiencies in Tnfa, Il6 and Cox2 expression following TLR2 stimulation. Furthermore, these macrophages did not express the TLR2-inducible gene set.
In this study, Akira and colleagues have shown that IRAK2 induces NF-κB-mediated transcription of inflammatory cytokines following TLR activation, and that IRAK2 activity is dependent on an intact kinase domain. While IRAK1 and IRAK2 have similar functions in the innate immune response, they display discrete temporal activation following TLR stimulation, as IRAK2 is dispensable in the early phase of signaling but required for sustained NF-κB activity.
Emily J. Chenette Signaling Gateway
References
Kawagoe, T. et al. Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nature Immunology9, 684-691 (2008) | Article | PubMed |
Meylan, E. & Tschopp, J. IRAK2 takes its place in TLR signaling. Nature Immunology9, 581-582 (2008) | Article | PubMed |
