Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and Toll-like receptor-mediated NF-κB activation
Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and Toll-like receptor-mediated NF-κB activation
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DOI：
10.1128/mcb.02098-07
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发表时间：
2008-05-01
影响因子：
5.3
通讯作者：
Ashwell, Jonathan D.
中科院分区：
文献类型：
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作者：
Conze, Dietrich B.;Wu, Chuan-Jin;Ashwell, Jonathan D.
通过白细胞介素-1受体（IL-1 R）和一些Toll样受体（TLR）的刺激诱导TRAF 6和IRAK-1的泛素化，TRAF 6和IRAK-1是NF-κ B和促分裂原活化蛋白激酶活化所需的信号传导组分。我们发现，尽管TRAF 6和IRAK-1在IL-1刺激后获得了Lys 63（K63）连接的多聚泛素链，但只有泛素化的IRAK-1结合了I κ B激酶（IKK）的调节亚基NEMO。IRAK-1泛素化位点定位于Lys 134和Lys][80，这些残基的精氨酸取代损害了IL-1 R/TLR介导的IRAK-1泛素化、NEMO结合和NF-κ B活化。IRAK-1的K63连接的泛素化需要具有酶活性的TRAF 6，这表明它是生理相关的E3。因此，近端信号蛋白的K63连接的多聚泛素化是多种先天免疫受体用于募集IKK和激活NF-κ B的常见机制。
Stimulation through the interleukin-1 receptor (IL-1R) and some Toll-like receptors (TLRs) induces ubiquitination of TRAF6 and IRAK-1, signaling components required for NF-kappa B and mitogen-activated protein kinase activation. Here we show that although TRAF6 and IRAK-I acquired Lys63 (K63)-linked polyubiquitin chains upon IL-1 stimulation, only ubiquitinated IRAK-1 bound NEMO, the regulatory subunit Of I kappa B kinase (IKK). The sites of IRAK-1 ubiquitination were mapped to Lys134 and Lys][80, and arginine substitution of these residues impaired IL-IR/TLR-mediated IRAK-1 ubiquitination, NEMO binding, and NF-kappa B activation. K63-linked ubiquitination of IRAK-1 required enzymatically active TRAF6, indicating that it is the physiologically relevant E3. Thus, K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-kappa B.