エネルギー・栄養感知と細胞分化・増殖シグナルハブとしてのライソゾーム新機能の解明

我发现位于溶酶体上的FLCN复合体调节TFE3的转录活性，从而上调代谢基因。我得到的线索支持FLCN-TFE3-HIF1a轴协调营养和缺氧信号的新概念如下。1) TFE3转录因子异常激活对缺氧反应通路的调控。我们已经报道了FLCN-TFE3轴通过代谢重编程调节细胞增殖和分化。在2020年，我阐明了异常激活的嵌合TFE3直接转录HIF1a和HIF2a，并上调缺氧反应基因。2) HIF1a在嵌合TFE3肿瘤发生中的重要作用。我将HIF1a和/或HIF2a条件KO小鼠与KI小鼠杂交，KI小鼠在肾脏中表达致癌嵌合TFE3。HIF1a敲除显著降低了肾肿瘤的发展，表明其作为嵌合tfe3下游分子的重要作用。3.3)脂质代谢途径作为TFE3-HIF1a轴的重要下游。我对用HIF1a和/或HIF2a敲除表达TFE3的嵌合肾脏进行了RNA测序。氧化石墨烯分析表明，嵌合TFE3的表达显著上调了参与脂质代谢的基因，而敲除HIF1a则下调了参与脂质代谢的基因。4) TFE3-mTORC1-HIF1a轴对脂质代谢的调控。我发现氨基酸饥饿和缺氧胁迫可以激活嵌合的TFE3-HIF转录轴，导致脂质代谢基因上调。

I have found that FLCN complex localizing on the lysosome regulates TFE3 transcriptional activity, which in turn upregulate metabolic genes. I have obtained a clue to support a new concept that FLCN-TFE3-HIF1a axis coordinate nutrient and hypoxia signaling as follows.1) Regulation of hypoxia response pathway by aberrantly activated TFE3 transcription factor. We have reported that FLCN-TFE3 axis regulates cell proliferation and differentiation through the metabolic reprogramming. In 2020, I clarified that aberrantly activated chimeric TFE3 directly transcribed HIF1a and HIF2a and upregulated hypoxia responsive genes.2) Essential role of HIF1a in tumorigenesis by a chimeric TFE3. I have crossed HIF1a and / or HIF2a conditional KO mice with KI mice which express oncogenic chimeric TFE3 in kidneys. HIF1a knockout significantly reduced kidney tumor development, indicating its essential role as a downstream molecule of chimeric TFE3.3) Lipid metabolism pathway as an important downstream of TFE3-HIF1a axis. I performed RNA sequencing on chimeric TFE3 expressing kidneys which were knockout with HIF1a and / or HIF2a. GO analysis demonstrated that genes involved in lipid metabolism were significantly upregulated by the expression of chimeric TFE3 and downregulated by knockingout HIF1a.4) Regulation of lipid metabolism by TFE3-mTORC1-HIF1a axis. I found that amino acid starvation and hypoxia stress could activate chimeric TFE3-HIF transcriptional axis, resulting in upregulation of lipid metabolism genes.