Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Sci Signal. 2010 Sep 28;3(141):pe34. doi: 10.1126/scisignal.3141pe34.
Tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) control inflammatory and immune responses by acting downstream of TNFRs and Toll-like receptors (TLRs). TRAF2 in particular has been extensively studied for its involvement in signaling by TNF-α, the classic inflammatory cytokine. Because it has a RING finger, it has been suggested that TRAF2 acts as an E3 ubiquitin ligase that catalyzes the noncanonical Lys-63 (K63)-linked polyubiquitination of receptor-induced protein 1 (RIP1), which is an essential event in the activation of the IκB kinase complex and consequently nuclear factor κB. Furthermore, TRAF2 itself is subject to K63-linked polyubiquitination, a modification that is rapidly induced upon receptor ligation and was interpreted to be the result of self-ubiquitination. However, formal evidence that TRAF2 is an active E3 ubiquitin ligase was lacking. New evidence shows that sphingosine-1-phosphate (S1P), a sphingolipid that is synthesized during inflammatory responses, is an essential cofactor for TRAF2 ubiquitin ligase activity. S1P binds to TRAF2 and promotes TRAF2-mediated K63-linked RIP1 polyubiquitination, providing direct evidence that TRAF2 is an active E3 ubiquitin ligase and also introducing lipid second messengers into the realm of TNFR and TLR signaling.
肿瘤坏死因子受体（TNFR）相关因子（TRAFs）通过作用于 TNFR 和 Toll 样受体（TLRs）下游来控制炎症和免疫反应。TRAF2 尤其因其参与 TNF-α（经典炎症细胞因子）信号转导而被广泛研究。由于它具有一个 RING 指结构，因此有人认为 TRAF2 作为一种 E3 泛素连接酶，可催化受体诱导蛋白 1（RIP1）的非典型 Lys-63（K63）连接多泛素化，这是激活 IκB 激酶复合物和随后的核因子 κB 的必要事件。此外，TRAF2 本身也受到 K63 连接多泛素化的修饰，这种修饰在受体结合后迅速诱导，被解释为自身泛素化的结果。然而，缺乏 TRAF2 是一种活性 E3 泛素连接酶的正式证据。新的证据表明，鞘氨醇-1-磷酸（S1P）是一种在炎症反应中合成的鞘脂，是 TRAF2 泛素连接酶活性的必需辅助因子。S1P 与 TRAF2 结合并促进 TRAF2 介导的 K63 连接的 RIP1 多泛素化，这提供了直接证据表明 TRAF2 是一种活性 E3 泛素连接酶，并将脂质第二信使引入 TNFR 和 TLR 信号转导领域。
