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

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• The tumor suppressor folliculin (FLCN) regulates nuclear translocation of TFE3, a key transcription factor for lysosomal biogenesis.
• The precise role of FLCN-mediated lysosomal regulation in mammalian physiology is not fully understood.

Purpose of the Study:

• To investigate the physiological importance of the FLCN-TFE3 pathway in controlling lysosome activity and preventing lysosomal storage disorders (LSDs).
• To elucidate the feedback mechanism between FLCN and TFE3 and its impact on cellular processes like glycogen metabolism.

Main Methods:

• Hematopoietic-lineage-specific deletion of the Flcn gene in mice.
• Analysis of cellular phenotypes, including phagocyte morphology and glycogen accumulation.
• Gene expression analysis of TFE3 and glycogenesis-related genes (Gys1, Gyg).
• Genetic deletion of Tfe3 in Flcn knockout mice to assess phenotypic rescue.

Main Results:

• Flcn deletion in mice led to the expansion of vacuolated phagocytes with cytoplasmic glycogen accumulation, mimicking LSD phenotypes.
• FLCN loss disrupts a feedback loop, increasing TFE3 activity and its target gene expression.
• TFE3 promotes glycogenesis by upregulating genes like Gys1 and Gyg upon Flcn loss.
• Tfe3 deletion ameliorated the LSD-like phenotypes observed in Flcn knockout mice.

Conclusions:

• The FLCN-TFE3 feedback loop functions as a critical rheostat controlling lysosome activity.
• This regulatory loop is essential for preventing excessive glycogenesis and the development of LSD-like phagocyte activation.
• Dysregulation of the FLCN-TFE3 pathway contributes to lysosomal storage disorders and metabolic abnormalities.