Nucleocytoplasmic Shuttling of FTO Does Not Affect Starvation-Induced Autophagy

Polymorphic variants of the FTO (fat mass and obesity) gene associate with body mass index in humans, but the underlying molecular mechanisms have not been firmly determined. FTO is linked to energy homeostasis via amino acid sensing and is thought to activate the mammalian target of rapamycin complex 1, a negative regulator of autophagy. FTO localises both to the nucleus and the cytoplasm, and in this study we identify a functional nuclear localisation signal (NLS) in the N-terminus of FTO, as well as nuclear localization information in its very C-terminus. Inhibition of FTO nuclear transport has no effect on autophagy and in contrast to a previously proposed role of FTO in autophagy, we find no difference in starvation-induced autophagy in control cells compared to a panel of cell types depleted of FTO. Future studies that further characterise the cellular functions of FTO will be important to understand why variants in FTO are associated with body weight.

人类体内FTO（fat mass and obesity）基因的多态性变异与体重指数（body mass index）存在关联，但其潜在分子机制尚未得到明确证实。FTO可通过氨基酸感知（amino acid sensing）途径参与能量稳态（energy homeostasis）调控，且被认为可激活哺乳动物雷帕霉素靶蛋白复合物1（mammalian target of rapamycin complex 1），该复合物是自噬（autophagy）的负调控因子。FTO可定位于细胞核（nucleus）与细胞质（cytoplasm）中，本研究在FTO的N端（N-terminus）鉴定出一段具有功能的核定位信号（nuclear localisation signal，NLS），同时在其极端C端（C-terminus）也发现了核定位相关信息。抑制FTO的核转运（nuclear transport）对自噬并无影响；与此前提出的FTO在自噬中的作用相悖，我们发现，在FTO敲除的一系列细胞类型与对照细胞中，饥饿诱导的自噬水平并无显著差异。未来若要明确FTO基因变异与体重关联的分子机制，进一步解析FTO的细胞功能将具有重要意义。