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Cell Rep. 2020 Feb 11;30(6):1823-1834.e5. doi: 10.1016/j.celrep.2020.01.042.

A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity.

Author information

1
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. Electronic address: mendoh@kumamoto-u.ac.jp.
2
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. Electronic address: babam@kumamoto-u.ac.jp.
3
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.
4
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
5
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.
6
International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
7
Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
8
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
9
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Basic Science Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21702, USA.
10
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. Electronic address: csits@nus.edu.sg.

Abstract

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.

KEYWORDS:

Birt-Hogg-Dubé Syndrome; Folliculin; Lysosomal storage disease; Lysosome; gluconeogenesis; glycogen; glycogenesis; hemophagocytosis

PMID:
32049013
DOI:
10.1016/j.celrep.2020.01.042
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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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