TFEB Phase Separation Mediates the Amelioration Effect of Intermittent Fasting on Inflammatory Colitis

Area of Science:

• Cell Biology
• Molecular Biology
• Immunology

Background:

• Intermittent fasting (IF) is known to reduce inflammation, including in DSS-induced colitis models.
• Autophagy is a key cellular process that limits inflammation.
• TFEB is a master transcriptional factor regulating autophagy, but its role in IF-mediated anti-inflammatory effects is unclear.

Purpose of the Study:

• To investigate the role of TFEB in the anti-inflammatory effects of intermittent fasting.
• To elucidate the mechanism by which TFEB mediates these effects, focusing on its phase separation properties.

Main Methods:

• Induction of DSS-induced colitis in a model system.
• Treatment with intermittent fasting (IF).
• Analysis of TFEB expression, localization, and phase separation using FRAP and 1,6-hexanediol assays.
• Investigation of TFEB's interaction with co-activators EP300 and MED1.
• Assessment of TFEB inhibitor effects on IF-mediated amelioration of colitis.

Main Results:

• IF ameliorated DSS-induced colitis and induced TFEB.
• Nutrition deprivation induced TFEB phase separation, dependent on specific amino acids in its N-terminal Coiled-Coil domain.
• Deletion of these amino acids impaired TFEB target gene expression.
• TFEB condensates formed transcriptional hubs with EP300 and MED1.
• Inhibition of TFEB phase separation abolished the anti-inflammatory effects of IF.

Conclusions:

• TFEB phase separation is a critical mechanism underlying the anti-inflammatory effects of intermittent fasting.
• TFEB acts as a transcriptional hub, facilitated by phase separation, to regulate genes involved in inflammation.
• Targeting TFEB phase separation offers a potential therapeutic strategy for inflammatory diseases.