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

  1. Author:
    Endoh, Mitsuhiro
    Baba, Masaya
    Endoh, Tamie
    Hirayama, Akiyoshi
    Nakamura-Ishizu, Ayako
    Umemoto, Terumasa
    Hashimoto, Michihiro
    Nagashima,Kunio
    Soga, Tomoyoshi
    Lang, Martin
    Schmidt,Laura
    Linehan, W Marston
    Suda, Toshio

  2. Author Address

    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., 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., Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan., 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., Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA., 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., 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.,
    1. Year: 2020
    2. Date: Feb 11
  2. Journal: Cell reports
    1. 30
    2. 6
    3. Pages: 1823-1834.e5
  4. Type of Article: Article
  5. ISSN: 2211-1247
  1. 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. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.celrep.2020.01.042
  3. PMID: 32049013
  4. View record in Web of Science®
  5. WOS: 000513920800014
  6. PII : S2211-1247(20)30066-8

Library Notes

  1. Fiscal Year: FY2019-2020
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