Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy.
Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, 80131, Naples, Italy.
Nat Commun. 2018 Aug 17;9(1):3312. doi: 10.1038/s41467-018-05862-6.
During starvation the transcriptional activation of catabolic processes is induced by the nuclear translocation and consequent activation of transcription factor EB (TFEB), a master modulator of autophagy and lysosomal biogenesis. However, how TFEB is inactivated upon nutrient refeeding is currently unknown. Here we show that TFEB subcellular localization is dynamically controlled by its continuous shuttling between the cytosol and the nucleus, with the nuclear export representing a limiting step. TFEB nuclear export is mediated by CRM1 and is modulated by nutrient availability via mTOR-dependent hierarchical multisite phosphorylation of serines S142 and S138, which are localized in proximity of a nuclear export signal (NES). Our data on TFEB nucleo-cytoplasmic shuttling suggest an unpredicted role of mTOR in nuclear export.
在饥饿状态下，转录因子 EB（TFEB）的核转位和随后的激活诱导了分解代谢过程的转录激活，TFEB 是自噬和溶酶体生物发生的主要调节因子。然而，目前尚不清楚营养再喂养时 TFEB 是如何失活的。在这里，我们表明 TFEB 的亚细胞定位是通过其在细胞质和细胞核之间的连续穿梭动态控制的，核输出是一个限制步骤。TFEB 的核输出是由 CRM1 介导的，并通过 mTOR 依赖性的丝氨酸 S142 和 S138 的分级多位点磷酸化来调节，这些磷酸化位于核输出信号 (NES) 附近。我们关于 TFEB 核质穿梭的研究结果表明 mTOR 在核输出中发挥了意想不到的作用。
