NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1.
NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1.
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NF-κB通过与核心时钟蛋白BMAL1的相互作用来修饰哺乳动物昼夜节律时钟。
DOI：
10.1371/journal.pgen.1009933
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发表时间：
2021-11
期刊：
影响因子：
4.5
通讯作者：
Liu AC
中科院分区：
文献类型：
--
作者：
Shen Y;Endale M;Wang W;Morris AR;Francey LJ;Harold RL;Hammers DW;Huo Z;Partch CL;Hogenesch JB;Wu ZH;Liu AC
在哺乳动物中，生物钟协调包括炎症在内的细胞生理过程。最近的研究表明，这两个途径之间的串扰。然而，炎症如何影响生物钟的机制尚不清楚。在此，我们研究了促炎转录因子NF-κB在调节生物钟功能中的作用。通过遗传学和药理学方法的结合，我们发现在人U2 OS细胞模型中，经典NF-κB亚基RELA的扰动改变了核心时钟基因的表达。而RELA激活缩短周期长度，抑制振幅，延长周期长度，造成振幅表型。NF-κB干扰也改变了主视交叉上核（SCN）生物钟的昼夜节律和不同光/暗条件下的运动活动行为。我们发现，RELA，像时钟阻遏物BMAL 1，抑制BMAL 1/CLOCK在昼夜节律的E盒顺式元件的转录活性。生化和生物物理分析表明，RELA结合BMAL 1的反式激活结构域。这些数据支持一个模型，其中NF-kB与BMAL 1和共激活因子CBP/p300竞争BMAL 1结合以影响昼夜节律转录。染色质免疫沉淀分析进一步支持了这一点，显示RELA、BMAL 1和CLOCK的结合集中在时钟基因的E盒上。综上所述，这些数据支持NF-κB在直接调节生物钟中的重要作用，并强调了生物钟和炎症通路之间的相互调节。生物钟协调日常细胞生理。有相当大的兴趣，在确定机制，细胞生理学的昼夜节律的时间保持。NF-κB是控制先天免疫和炎症的主要网络枢纽。NF-κB的慢性组成性激活是许多人类疾病和病症如免疫疾病、代谢紊乱、神经变性疾病、癌症和衰老的主要原因之一。本研究探讨了NF-κB在调节中枢和外周生物钟中的作用。使用遗传学和药理学方法的组合，我们表明，NF-κB扰动改变细胞和组织中的时钟振荡，以及在小鼠中。此外，使用生物化学和生物物理学方法，我们表明，NF-κ B直接结合到BMAL 1的反式激活结构域，其中时钟辅助调节因子CBP/p300和CRY结合;因此，像CRY一样，NF-κ B抑制E盒转录。总之，这些结果支持NF-κ B在将炎症与昼夜节律计时联系起来方面的重要作用。
In mammals, the circadian clock coordinates cell physiological processes including inflammation. Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the clock is not well understood. Here, we investigated the role of the proinflammatory transcription factor NF-κB in regulating clock function. Using a combination of genetic and pharmacological approaches, we show that perturbation of the canonical NF-κB subunit RELA in the human U2OS cellular model altered core clock gene expression. While RELA activation shortened period length and dampened amplitude, its inhibition lengthened period length and caused amplitude phenotypes. NF-κB perturbation also altered circadian rhythms in the master suprachiasmatic nucleus (SCN) clock and locomotor activity behavior under different light/dark conditions. We show that RELA, like the clock repressor CRY1, repressed the transcriptional activity of BMAL1/CLOCK at the circadian E-box cis-element. Biochemical and biophysical analysis showed that RELA binds to the transactivation domain of BMAL1. These data support a model in which NF-kB competes with CRY1 and coactivator CBP/p300 for BMAL1 binding to affect circadian transcription. This is further supported by chromatin immunoprecipitation analysis showing that binding of RELA, BMAL1 and CLOCK converges on the E-boxes of clock genes. Taken together, these data support a significant role for NF-κB in directly regulating the circadian clock and highlight mutual regulation between the circadian and inflammatory pathways. The circadian clock coordinates daily cell physiology. There has been considerable interest in identifying mechanisms that link cell physiology to circadian time-keeping. NF-κB is a major network hub controlling innate immunity and inflammation. Chronic constitutive activation of NF-κB is one of the primary causes of a number of human diseases and conditions such as immune diseases, metabolic disorders, neurodegenerative diseases, cancer and aging. Here we investigated the role of NF-κB in regulating the central and peripheral circadian clocks. Using a combination of genetic and pharmacological approaches we show that NF-κB perturbation alters clock oscillations in cells and tissues, as well as in mice. Further, using biochemical and biophysical methods, we show that NF-kB directly binds to the transactivation domain of BMAL1 where clock coregulators CBP/p300 and CRY bind; and as a result, like CRY, NF-kB represses E-box transcription. Together, these results support a significant role for NF-kB in linking inflammation to circadian timekeeping.
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影响因子：
16
作者：
Gustafson CL;Parsley NC;Asimgil H;Lee HW;Ahlbach C;Michael AK;Xu H;Williams OL;Davis TL;Liu AC;Partch CL
通讯作者：
Partch CL
影响因子：
8
作者：
Hammers, David W.;Sleeper, Margaret M.;Sweeney, H. Lee
通讯作者：
Sweeney, H. Lee
影响因子：
4.8
作者：
Kaileh, Mary;Vanden Berghe, Wim;Haegeman, Guy
通讯作者：
Haegeman, Guy
影响因子：
4.8
作者：
Khan, Sanjoy K.;Xu, Haiyan;Liu, Andrew C.
通讯作者：
Liu, Andrew C.
DOI：
10.1126/science.1222804
发表时间：
2012-07-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Huang N;Chelliah Y;Shan Y;Taylor CA;Yoo SH;Partch C;Green CB;Zhang H;Takahashi JS
通讯作者：
Takahashi JS