Fat mass and obesity-related (FTO) shuttles between the nucleus and cytoplasm.
Fat mass and obesity-related (FTO) shuttles between the nucleus and cytoplasm.
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DOI：
10.1042/bsr20140111
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发表时间：
2014-10-22
影响因子：
4
通讯作者：
Yeo GS
中科院分区：
文献类型：
--
作者：
Gulati P;Avezov E;Ma M;Antrobus R;Lehner P;O'Rahilly S;Yeo GS
包括FTO、IRX3、5、6、FTM和FTL在内的16号染色体上的SNPs(单核苷酸多态)与人类肥胖密切相关。FTO催化依赖于Fe(II)和2OG的RNA去甲基化，是一种AA(氨基酸)传感器，将AA水平与mTORC1(雷帕霉素复合体1的哺乳动物靶标)信号连接起来，从而在调节生长和翻译方面发挥关键作用。然而，FTO主要存在于哪个细胞隔间以发挥其生化作用尚不清楚。在这里，我们进行了GFP(绿色荧光蛋白)-FTO的活细胞成像，并证明FTO既存在于细胞核中，也存在于细胞质中。我们显示使用‘翻转’(光漂白中的荧光损失)，一个流动的FTO部分在两个隔间之间穿梭。我们进行了蛋白质组学研究，并确定XPO2(Exportin 2)是FTO的结合伙伴，XPO2(Exportin 2)是介导蛋白质在细胞核和细胞质之间穿梭的蛋白质家族之一。最后，通过缺失研究，我们发现FTO的N末端是其穿梭于细胞核和细胞质之间所必需的。总之，FTO既存在于细胞核中，也存在于细胞质中，可能通过与XPO2的相互作用，在两个细胞间穿梭。Exportin与FTO相互作用，这种相互作用可能与FTO在细胞内的核质穿梭有关。
SNPs (single nucleotide polymorphisms) on a chromosome 16 locus encompassing FTO, as well as IRX3, 5, 6, FTM and FTL are robustly associated with human obesity. FTO catalyses the Fe(II)- and 2OG-dependent demethylation of RNA and is an AA (amino acid) sensor that couples AA levels to mTORC1 (mammalian target of rapamycin complex 1) signalling, thereby playing a key role in regulating growth and translation. However, the cellular compartment in which FTO primarily resides to perform its biochemical role is unclear. Here, we undertake live cell imaging of GFP (green fluorescent protein)-FTO, and demonstrate that FTO resides in both the nucleus and cytoplasm. We show using ‘FLIP’ (fluorescence loss in photobleaching) that a mobile FTO fraction shuttles between both compartments. We performed a proteomic study and identified XPO2 (Exportin 2), one of a family of proteins that mediates the shuttling of proteins between the nucleus and the cytoplasm, as a binding partner of FTO. Finally, using deletion studies, we show that the N-terminus of FTO is required for its ability to shuttle between the nucleus and cytoplasm. In conclusion, FTO is present in both the nucleus and cytoplasm, with a mobile fraction that shuttles between both cellular compartments, possibly by interaction with XPO2. Exportin interacts with FTO and this interaction might be involved in the nucelocytoplasmic shuttling of FTO in the cell.