IL-1 receptor-associated kinase-2 genetic variant rs708035 increases NF-{kappa}B activity through promoting TRAF6 ubiquitination [Signal Transduction]

March 24th, 2014 by Zhang, W., He, T., Wang, Q., Li, X., Wei, J., Hou, X., Zhang, B., Huang, L., Wang, L.

The IL-1 Receptor-Associated Kinases (IRAKs) are key regulators of Toll-like receptor (TLR) /IL-1 signaling, which are critical regulators of mammalian inflammation and innate immune response. Single nucleotide polymorphisms (SNPs) within the IRAK genes have been discovered recently. However, the functions of these IRAK SNPs remain largely unknown. Here, we found that the non-synonymous IRAK2 variant, rs708035 (coding D431E), increases NF-κB activity and leads to more expression of NF-κB dependent pro-inflammatory cytokines compared to IRAK2 wide type. Moreover, when IRAK2 knocking down cells reconstituted with siRNA-resistant WT-IRAK2 or D431E-IRAK2 were infected with influenza virus, more obvious induction of IL-6 and a stronger anti-apoptosis effect were observed in D431E IRAK2 expressing cells. Notably, we also found that the levels of pro-inflammatory cytokine-IL-6 were indeed higher in people carring D431E-IRAK2 than those carring WT-IRAK2. Further study demonstrated that the elevated NF-κB activation mediated by IRAK2 variant was due to increased TRAF6 ubiquitination and faster IκB-α-degradation. Our study provides an important insight of IRAK2 SNP in the regulation of NF-κB activation and indicates that the IRAK2 rs708035 might be associated with human diseases caused by hyper-activation of NF-κB
  • Posted in Journal of Biological Chemistry, Publications
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