title: Interaction of nucleosome assembly proteins abolishes nuclear localization of DGKζ by attenuating its association with importins.
abstract: 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.
authors: Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
authors: Masashi
authors: M
authors: Okada
authors: Yasukazu
authors: Y
authors: Hozumi
authors: Tohru
authors: T
authors: Ichimura
authors: Toshiaki
authors: T
authors: Tanaka
authors: Hiroshi
authors: H
authors: Hasegawa
authors: Masakazu
authors: M
authors: Yamamoto
authors: Nobuya
authors: N
authors: Takahashi
authors: Ken
authors: K
authors: Iseki
authors: Hitoshi
authors: H
authors: Yagisawa
authors: Takashi
authors: T
authors: Shinkawa
authors: Toshiaki
authors: T
authors: Isobe
authors: Kaoru
authors: K
authors: Goto
mesh_terms: D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056490:Nucleosome Assembly Protein 1 / Q000235:genetics / Q000378:metabolism*; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D021381:Protein Transport; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D028901:alpha Karyopherins / Q000378:metabolism
chemical_list: C423142:KPNA1 protein, human; C106259:KPNA4 protein, human; D028884:Karyopherins; C533557:NAP1L1 protein, human; C104356:NAP1L4 protein, human; D009687:Nuclear Proteins; D056490:Nucleosome Assembly Protein 1; D009707:Nucleosomes; D028901:alpha Karyopherins; C526463:DGKZ protein, human; D019852:Diacylglycerol Kinase