Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Singapore; International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Cell Rep. 2020 Feb 11;30(6):1823-1834.e5. doi: 10.1016/j.celrep.2020.01.042.
The tumor suppressor folliculin (FLCN) suppresses nuclear translocation of TFE3, a master transcription factor for lysosomal biogenesis, via regulation of amino-acid-sensing Rag GTPases. However, the importance of this lysosomal regulation in mammalian physiology remains unclear. Following hematopoietic-lineage-specific Flcn deletion in mice, we found expansion of vacuolated phagocytes that accumulate glycogen in their cytoplasm, phenotypes reminiscent of lysosomal storage disorder (LSD). We report that TFE3 acts in a feedback loop to transcriptionally activate FLCN expression, and FLCN loss disrupts this loop, augmenting TFE3 activity. Tfe3 deletion in Flcn knockout mice reduces the number of phagocytes and ameliorates LSD-like phenotypes. We further reveal that TFE3 stimulates glycogenesis by promoting the expression of glycogenesis genes, including Gys1 and Gyg, upon loss of Flcn. Taken together, we propose that the FLCN-TFE3 feedback loop acts as a rheostat to control lysosome activity and prevents excessive glycogenesis and LSD-like phagocyte activation.
抑癌基因成纤维细胞生长因子受体底物 2（FLCN）通过调节氨基酸感应 Rag GTPase 抑制核转位 TFE3，后者是溶酶体生物发生的主要转录因子。然而，这种溶酶体调节在哺乳动物生理学中的重要性仍不清楚。在小鼠中进行造血谱系特异性 Flcn 缺失后，我们发现空泡化吞噬细胞的扩张，其细胞质中积累糖原，其表型类似于溶酶体贮积病（LSD）。我们报告 TFE3 在反馈回路中起作用，转录激活 FLCN 的表达，而 FLCN 的缺失破坏了这个回路，增加了 TFE3 的活性。在 Flcn 敲除小鼠中删除 Tfe3 可减少吞噬细胞的数量，并改善 LSD 样表型。我们进一步揭示 TFE3 通过促进糖生成基因（包括 Gys1 和 Gyg）的表达来刺激糖生成，在 Flcn 缺失时。总之，我们提出 FLCN-TFE3 反馈回路作为变阻器来控制溶酶体活性，并防止过度糖生成和 LSD 样吞噬细胞激活。
