TY - JOUR
T1 - A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity
AU - Endoh, Mitsuhiro
AU - Baba, Masaya
AU - Endoh, Tamie
AU - Hirayama, Akiyoshi
AU - Nakamura-Ishizu, Ayako
AU - Umemoto, Terumasa
AU - Hashimoto, Michihiro
AU - Nagashima, Kunio
AU - Soga, Tomoyoshi
AU - Lang, Martin
AU - Schmidt, Laura S.
AU - Linehan, W. Marston
AU - Suda, Toshio
N1 - Funding Information:
This research is supported by the National Research Foundation of Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. T. Suda was supported by a Singapore Translational Research (STaR) Investigator Award from the National Research Foundation of Singapore ( NMRC/STaR/019/2014 and NMRC/STaR/18 may-0004 ) and in part by JSPS KAKENHI Grant-in-Aid for Scientific Research (S) (grant 26221309 ). M.E. was supported by JSPS KAKENHI Grants-in-Aid for Scientific Research (C) (grants 19K06693 and 16K07372 ) from the Ministry of Education, Culture, Sports, Science and Technology [ MEXT ] of Japan. M.B. was supported in part by JSPS KAKENHI Grants-in-Aid for Scientific Research (S, grants 18H05284 and 26221309 ; B, grant 18H02938 ; and C, 18K09140 ), a Grant-in-Aid for Challenging Research (exploratory; grants 18K19619 and 18K19553 ), the Joint Usage/Research Center Program of the Advanced Medical Research Center, Yokohama City University (Yokohama, Japan), and the program of the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University (Kumamoto, Japan). This project was funded in part by federal funds from the Frederick National Laboratory for Cancer Research ( NIH ) under contract HHSN261200800001E (L.S.S.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported by the Intramural Research Program of the NIH , National Cancer Institute, Center for Cancer Research.
Funding Information:
This research is supported by the National Research Foundation of Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. T. Suda was supported by a Singapore Translational Research (STaR) Investigator Award from the National Research Foundation of Singapore (NMRC/STaR/019/2014 and NMRC/STaR/18 may-0004) and in part by JSPS KAKENHI Grant-in-Aid for Scientific Research (S) (grant 26221309). M.E. was supported by JSPS KAKENHI Grants-in-Aid for Scientific Research (C) (grants 19K06693 and 16K07372) from the Ministry of Education, Culture, Sports, Science and Technology [MEXT] of Japan. M.B. was supported in part by JSPS KAKENHI Grants-in-Aid for Scientific Research (S, grants 18H05284 and 26221309; B, grant 18H02938; and C, 18K09140), a Grant-in-Aid for Challenging Research (exploratory; grants 18K19619 and 18K19553), the Joint Usage/Research Center Program of the Advanced Medical Research Center, Yokohama City University (Yokohama, Japan), and the program of the Joint Usage/Research Center for Developmental Medicine, Institute of Molecular Embryology and Genetics, Kumamoto University (Kumamoto, Japan). This project was funded in part by federal funds from the Frederick National Laboratory for Cancer Research (NIH) under contract HHSN261200800001E (L.S.S.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. M.E. M.B. and T. Suda conceived the project. M.E. M.B. and T.E. designed and performed most experiments with input from L.S.S. W.M.L. and T. Suda. T.U. and M.H. performed fluorescence-activated cell sorting (FACS) analysis of hematopoietic lineage cells and participated in discussions of results. A.N.I. and K.N. performed and interpreted electron microscopy experiments. A.H. and T. Soga performed and interpreted metabolomics experiments. M.L. performed PAS staining of kidney sections from BHD patients. M.E. wrote the manuscript, which was edited by M.B. L.S.S. W.M.L. and T. Suda, with help from other authors. The authors declare no competing interests.
Publisher Copyright:
© 2020 The Authors
PY - 2020/2/11
Y1 - 2020/2/11
N2 - 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. Endoh et al. show that hematopoietic-lineage-specific FLCN deletion in mice induces expansion of phagocytes accumulating cytoplasmic glycogen. TFE3 acts in a feedback loop to activate FLCN expression, and FLCN loss disrupts this loop, augmenting TFE3 activity. TFE3 deletion in FLCN knockout mice blocks aberrant glycogenesis and ameliorates the phenotypes.
AB - 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. Endoh et al. show that hematopoietic-lineage-specific FLCN deletion in mice induces expansion of phagocytes accumulating cytoplasmic glycogen. TFE3 acts in a feedback loop to activate FLCN expression, and FLCN loss disrupts this loop, augmenting TFE3 activity. TFE3 deletion in FLCN knockout mice blocks aberrant glycogenesis and ameliorates the phenotypes.
KW - Birt-Hogg-Dubé Syndrome
KW - Folliculin
KW - Lysosomal storage disease
KW - Lysosome
KW - gluconeogenesis
KW - glycogen
KW - glycogenesis
KW - hemophagocytosis
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U2 - 10.1016/j.celrep.2020.01.042
DO - 10.1016/j.celrep.2020.01.042
M3 - Article
C2 - 32049013
AN - SCOPUS:85079191176
SN - 2211-1247
VL - 30
SP - 1823-1834.e5
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -