TFEB-driven endocytosis coordinates MTORC1 signaling and autophagy

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Mechanistic target of rapamycin kinase complex 1 (MTORC1) regulates cellular anabolism and catabolism, including autophagy and lysosomal biogenesis.
• Transcription factor EB (TFEB) is a key regulator of these processes, influencing MTORC1 activity and lysosomal function.

Purpose of the Study:

• To investigate the role of TFEB in cellular endocytosis.
• To elucidate the mechanism by which TFEB-mediated endocytosis impacts MTORC1 activation and nutrient sensing.

Main Methods:

• Assessed TFEB's effect on endocytic gene expression and cellular endocytosis rates under homeostatic and starvation conditions.
• Utilized co-immunoprecipitation and microscopy to analyze the formation of TFEB-induced signaling endosomes and their association with MTORC1 components (RRAGD, SLC38A9, AKT).
• Investigated the role of these endosomes in MTORC1 activation by examining TSC2 dissociation and MTORC1 re-tethering to endolysosomal membranes.

Main Results:

• TFEB significantly promotes the expression of endocytic genes and increases endocytosis rates.
• TFEB-mediated endocytosis facilitates the assembly of a nutrient-sensing complex containing MTORC1, RRAGD, SLC38A9, and activated AKT.
• TFEB-induced signaling endosomes, upon amino acid starvation, are essential for MTORC1 activation on endolysosomal membranes by promoting TSC2 dissociation and MTORC1 re-tethering.

Conclusions:

• TFEB-mediated endocytosis is a critical pathway for activating MTORC1 signaling.
• This process is vital for nutrient sensing and subsequent autophagic function.
• The study underscores the importance of the dynamic endolysosomal system in maintaining cellular homeostasis and clearance.