Regulation of NF-κB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA
Regulation of NF-κB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA
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DOI：
10.1016/s1097-2765(03)00490-8
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发表时间：
2003-12-01
期刊：
影响因子：
16
通讯作者：
Lu, KP
中科院分区：
文献类型：
--
作者：
Ryo, A;Suizu, F;Lu, KP
转录因子NF-κ B通过其抑制剂IB的降解而被激活，导致其核转位。然而，核NF-κ B随后调节的机制尚不清楚。在这里，我们表明，NF-κ B功能的Pin 1介导的脯氨酰异构化和泛素介导的p65/RelA亚基的蛋白水解调节。细胞因子处理后，Pin 1与p65中的pThr 254-Pro基序结合并抑制p65与IkappaB α结合，导致p65的核积累和蛋白稳定性增加以及NF-κ B活性增强。值得注意的是，Pin 1缺陷型小鼠和细胞对细胞因子信号引起的NF-κ B活化是难治的。此外，p65的稳定性由泛素介导的蛋白水解控制，由细胞因子信号抑制剂SOCS-1作为泛素连接酶促进。这些发现揭示了调节NF-kappaB信号传导的两种重要机制，并为某些人类疾病（如癌症）的发病机制和治疗提供了新的见解。
The transcription factor NF-kappaB is activated by the degradation of its inhibitor IB, resulting in its nuclear translocation. However, the mechanism by which nuclear NF-kappaB is subsequently regulated is not clear. Here we demonstrate that NF-kappaB function is regulated by Pin1-mediated prolyl isomerization and ubiquitin-mediated proteolysis of its p65/RelA subunit. Upon cytokine treatment, Pin1 binds to the pThr254-Pro motif in p65 and inhibits p65 binding to IkappaBalpha, resulting in increased nuclear accumulation and protein stability of p65 and enhanced NF-kappaB activity. Significantly, Pin1-deficient mice and cells are refractory to NF-kappaB activation by cytokine signals. Moreover, the stability of p65 is controlled by ubiquitin-mediated proteolysis, facilitated by a cytokine signal inhibitor, SOCS-1, acting as a ubiquitin ligase. These findings uncover two important mechanisms of regulating NF-kappaB signaling and offer new insight into the pathogenesis and treatment of some human diseases such as cancers.