mTORC1 feedback to AKT modulates lysosomal biogenesis through MiT/TFE regulation

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• The microphthalmia family of transcription factors (MiT/TFEs) regulate lysosomal biogenesis.
• The nutrient sensor mTORC1 negatively regulates MiT/TFEs.
• Mechanisms maintaining lysosomal catabolism during constitutive mTORC1 signaling are unclear.

Purpose of the Study:

• To elucidate how cells with constitutive mTORC1 signaling maintain lysosomal catabolism.
• To investigate the role of feedback loops in regulating lysosomal content under varying mTORC1 activity.

Main Methods:

• Utilized a murine epidermis model with epidermal Tsc1 deletion to induce constitutive mTORC1 activation.
• Analyzed EGFR and HER2 degradation, lysosomal content, and MiT/TFE expression and activity.
• Investigated the impact of genetic deletion of Rheb or Rptor and pharmacologic mTORC1 inactivation.
• Examined the role of AKT signaling in mediating mTORC1 effects on MiT/TFEs.

Main Results:

• Epidermal Tsc1 deletion led to wavy hair, curly whiskers, and increased EGFR/HER2 degradation.
• Constitutive mTORC1 activation unexpectedly increased lysosomal content via upregulated MiT/TFEs.
• Feedback inhibition of AKT suppressed AKT-induced MiT/TFE downregulation, mediating the paradoxical increase in lysosomal biogenesis.
• Inhibition of hyperactive AKT signaling restored MiT/TFE expression and activity in mTORC1 loss-of-function contexts.

Conclusions:

• Signaling feedback loops maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling.
• mTORC1 regulates upstream receptor tyrosine kinase signaling through feedback mechanisms.
• This study reveals a novel mechanism by which mTORC1 influences lysosomal biogenesis and receptor tyrosine kinase degradation.