Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain
Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain
复制标题
DOI：
10.1101/gad.13.10.1297
复制
发表时间：
1999-05-15
影响因子：
10.5
通讯作者：
Karin, M
中科院分区：
文献类型：
--
作者：
Baud, V;Liu, ZG;Karin, M
白细胞介素-1（IL-1）和肿瘤坏死因子（TNF-α）分别通过激活MAP激酶JNK和p38以及I κ B激酶（IKK）来刺激转录因子AP-1和NF-κ B。TNF-α和IL-1信号分别通过TRAF 2和TRAF 6转导。过表达的TRAF 2或TRAF 6在没有细胞外刺激的情况下激活JNK、p38或IKK。通过用亲免素FKBP 12的重复序列替换TRAF 2和TRAF 6的羧基末端TRAF结构域，我们证明了它们的效应器结构域由它们的氨基末端Zn和RING指组成。TRAF 2效应结构域的寡聚化导致与MEKK 1特异性结合，MEKK 1是一种能够激活JNK、p38和IKK的蛋白激酶，并诱导TNF-α和IL-1应答基因。TNF-α还增强天然TRAF 2与MEKK 1的结合，并刺激后者的激酶活性。因此，TNF-α和IL-1信号传导基于TRAF 2和TRAF 6的寡聚化，导致效应激酶的激活。
Interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha) stimulate transcription factors AP-1 and NF-kappa B through activation of the MAP kinases JNK and p38 and the I kappa B kinase (IKK), respectively. The TNF-alpha and IL-1 signals are transduced through TRAF2 and TRAF6, respectively. Overexpressed TRAF2 or TRAF6 activate JNK, p38, or IKK in the absence of extracellular stimulation. By replacing the carboxy-terminal TRAF domain of TRAF2 and TRAF6 with repeats of the immunophilin FKBP12, we demonstrate that their effector domains are composed of their amino-terminal Zn and RING fingers. Oligomerization of the TRAF2 effector domain results in specific binding to MEKK1, a protein kinase capable of JNK, p38, and IKK activation, and induction of TNF-alpha and IL-1 responsive genes. TNF-alpha also enhances the binding of native TRAF2 to MEKK1 and stimulates the kinase activity of the latter. Thus, TNF-alpha and IL-1 signaling is based on oligomerization of TRAF2 and TRAF6 leading to activation of effector kinases.