Interaction of nucleosome assembly proteins abolishes nuclear localization of DGKζ by attenuating its association with importins.
Interaction of nucleosome assembly proteins abolishes nuclear localization of DGKζ by attenuating its association with importins.
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DOI：
10.1016/j.yexcr.2011.09.014
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发表时间：
2011-12
影响因子：
3.7
通讯作者：
M. Okada;Y. Hozumi;T. Ichimura;Toshiaki Tanaka;H. Hasegawa;Masakazu Yamamoto;Nobuya Takahashi;K. Iseki;H. Yagisawa;T. Shinkawa;T. Isobe;K. Goto
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文献类型：
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作者：
M. Okada;Y. Hozumi;T. Ichimura;Toshiaki Tanaka;H. Hasegawa;Masakazu Yamamoto;Nobuya Takahashi;K. Iseki;H. Yagisawa;T. Shinkawa;T. Isobe;K. Goto
甘油二酯激酶（DGK）通过第二信使甘油二酯的代谢参与调节脂质介导的信号转导。在DGK家族中，含有核定位信号的DGK β主要定位于细胞核，但在病理条件下易位至细胞质。然而，详细的易位机制及其功能意义仍不清楚。为了阐明这些问题，我们使用蛋白质组学方法来寻找与DGK β相互作用的蛋白质靶点。结果表明，核小体组装蛋白（NAP）1-like 1（NAP 1 L1）和NAP 1-like 4（NAP 1 L4）被鉴定为新的DGK β结合伴侣。在转染的HEK 293细胞中，NAP 1 Ls组成性地穿梭于细胞核和细胞质之间。DGK β和NAP 1 Ls的分子相互作用阻止了DGK β的核输入，因为NAP 1 Ls与DGK β的结合阻断了输入载体蛋白Qip 1和NPI 1与DGK β的相互作用，导致DGK β的细胞质束缚。此外，NAP 1 Ls的过表达对阿霉素诱导的细胞毒性发挥保护作用。这些结果表明，NAP 1 Ls参与了一个新的分子基础，为调节DGK的核质穿梭，并提供了一个线索，以检查其易位在病理条件下的功能意义。
Diacylglycerol kinase (DGK) is involved in the regulation of lipid-mediated signal transduction through the metabolism of a second messenger diacylglycerol. Of the DGK family, DGKζ, which contains a nuclear localization signal, localizes mainly to the nucleus but translocates to the cytoplasm under pathological conditions. However, the detailed mechanism of translocation and its functional significance remain unclear. To elucidate these issues, we used a proteomic approach to search for protein targets that interact with DGKζ. Results show that nucleosome assembly protein (NAP) 1-like 1 (NAP1L1) and NAP1-like 4 (NAP1L4) are identified as novel DGKζ binding partners. NAP1Ls constitutively shuttle between the nucleus and the cytoplasm in transfected HEK293 cells. The molecular interaction of DGKζ and NAP1Ls prohibits nuclear import of DGKζ because binding of NAP1Ls to DGKζ blocks import carrier proteins, Qip1 and NPI1, to interact with DGKζ, leading to cytoplasmic tethering of DGKζ. In addition, overexpression of NAP1Ls exerts a protective effect against doxorubicin-induced cytotoxicity. These findings suggest that NAP1Ls are involved in a novel molecular basis for the regulation of nucleocytoplasmic shuttling of DGKζ and provide a clue to examine functional significance of its translocation under pathological conditions.