Cytoplasmic IκBα increases NF-κB-independent transcription through binding to histone deacetylase (HDAC) 1 and HDAC3
Cytoplasmic IκBα increases NF-κB-independent transcription through binding to histone deacetylase (HDAC) 1 and HDAC3
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DOI：
10.1074/jbc.m306381200
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发表时间：
2003-11-21
影响因子：
4.8
通讯作者：
Chariot, A
中科院分区：
文献类型：
--
作者：
Viatour, P;Legrand-Poels, S;Chariot, A
IkappaBalpha是一种抑制分子，它将核因子-kappaB二聚体隔离在未受刺激的细胞的细胞质中。在刺激下，核因子-kappaB移动到细胞核，并诱导包括IkappaBalpha在内的各种基因的表达。这种新合成的IkappaBalpha还可以移位到细胞核，将激活的NF-kappaB从其靶基因上移除，并将其带回细胞质，以终止NF-kappaB的激活阶段。我们在这里展示了IkappaBalpha通过与组蛋白脱乙酰酶(HDAC)1和HDAC3而不是与HDAC2、-4、-5和-6非依赖于NF-kappaB的结合来增强几种含有同源结构域的蛋白如HOXB7和Pit-1的反式激活潜力。IkappaBalpha通过其锚蛋白重复序列与这两种HDAC蛋白结合，这种相互作用被p65破坏。免疫荧光实验进一步证明，IkappaBalpha通过将HDAC3部分重定向到细胞质来发挥作用。同时，缺乏功能性核定位序列的IkappaBalpha突变体可以非常有效地与HDAC1和-3相互作用，并显著增强Pit-1的反式激活潜能。我们的结果支持这样的假设，即NF-kappaB抑制剂IkappaBalpha通过细胞质隔离HDAC1和HDAC3正向调节含有同源结构域的蛋白质的转录活性，这一机制将赋予IkappaBalpha一个新的和意想不到的作用。
IkappaBalpha is an inhibitory molecule that sequesters NF-kappaB dimers in the cytoplasm of unstimulated cells. Upon stimulation, NF-kappaB moves to the nucleus and induces the expression of a variety of genes including IkappaBalpha. This newly synthesized IkappaBalpha also translocates to the nucleus, removes activated NF-kappaB from its target genes, and brings it back to the cytoplasm to terminate the phase of NF-kappaB activation. We show here that IkappaBalpha enhances the transactivation potential of several homeodomain- containing proteins such as HOXB7 and Pit- 1 through a NF-kappaB- independent association with histone deacetylase ( HDAC) 1 and HDAC3 but not with HDAC2, - 4, - 5, and - 6. IkappaBalpha bound both HDAC proteins through its ankyrin repeats, and this interaction was disrupted by p65. Immunofluorescence experiments demonstrated further that IkappaBalpha acts by partially redirecting HDAC3 to the cytoplasm. At the same time, an IkappaBalpha mutant, which lacked a functional nuclear localization sequence, interacted very efficiently with HDAC1 and - 3 and intensively enhanced the transactivation potential of Pit- 1. Our results support the hypothesis that the NF-kappaB inhibitor IkappaBalpha regulates the transcriptional activity of homeodomain- containing proteins positively through cytoplasmic sequestration of HDAC1 and HDAC3, a mechanism that would assign a new and unexpected role to IkappaBalpha.