Kruppel-Associated Box-Associated Protein 1 Negatively Regulates TNF-α-Induced NF-κB Transcriptional Activity by Influencing the Interactions among STAT3, p300, and NF-κB/p65
Kruppel-Associated Box-Associated Protein 1 Negatively Regulates TNF-α-Induced NF-κB Transcriptional Activity by Influencing the Interactions among STAT3, p300, and NF-κB/p65
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DOI：
10.4049/jimmunol.1003243
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发表时间：
2011-09-01
影响因子：
4.4
通讯作者：
Matsuda, Tadashi
中科院分区：
文献类型：
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作者：
Kamitani, Shinya;Togi, Sumihito;Matsuda, Tadashi
Kruppel相关盒相关蛋白1（KAP 1）被认为主要作为蛋白质复合物的支架，这些蛋白质复合物通过触发异染色质的形成来沉默转录。使用小干扰RNA介导的KAP 1敲低，我们发现内源性KAP 1负调控HeLa细胞中TNF-α诱导的IL-6产生。KAP 1可能调节NF-κ B B与IL-6启动子的结合，因为KAP 1敲低增强TNF-α诱导的NF-κ B-荧光素酶活性，但不增强Ik κ B α降解。重要的是，我们发现KAP 1对STAT 3的丝氨酸磷酸化、NF-κ B B/p65通过p300的乙酰化以及NF-κ B/p65的核定位具有负调节作用。此外，KAP 1与NF-κ B/p65相关，并抑制NF-κ B/p65与p300的结合。因此，KAP 1可能负性控制NF-κ B B/p65的乙酰化，这对其核保留至关重要。总之，KAP 1通过干扰STAT 3、p300和NF-κ B/p65之间的相互作用来调节NF-κ B/p65的乙酰化，导致TNF-α刺激后IL-6的产生减少。我们的发现，KAP 1直接与转录因子相互作用是新的，并将为进一步的研究，以阐明KAP 1的功能。免疫学杂志，2011，187：2476-2483。
Kruppel-associated box-associated protein 1 (KAP1) is thought to act mainly as a scaffold for protein complexes, which together silence transcription by triggering the formation of heterochromatin. Using small interfering RNA-mediated KAP1 knockdown, we found that endogenous KAP1 negatively regulated TNF-alpha-induced IL-6 production in HeLa cells. KAP1 is likely to modulate the binding of NF-kappa B to the IL-6 promoter because KAP1 knockdown enhanced TNF-a-induced NF-kappa B-luciferase activity, but not Ik kappa B alpha degradation. Of importance, we found negative regulatory effects of KAP1 on the serine phosphorylation of STAT3, the acetylation of NF-kappa B/p65 by p300, and the nuclear localization of NF-kappa B/p65. In addition, KAP1 associated with NF-kappa B/p65 and inhibited the binding between NF-kappa B/p65 and p300. Thus, KAP1 is likely to negatively control the acetylation of NF-kappa B/p65, which is critical for its nuclear retention. Taken together, KAP1 modulated the acetylation of NF-kappa B/p65 by interfering with the interactions among STAT3, p300, and NF-kappa B/p65, resulting in reduced IL-6 production after TNF-alpha stimulation. Our findings that KAP1 directly interacts with transcriptional factors are new, and will inform further research to elucidate KAP1 function. The Journal of Immunology, 2011, 187: 2476-2483.