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

Overview

Journal Inflammation

Specialties Allergy & Immunology
Pathology

Date 2024 Dec 27

PMID 39729151

Authors

Xiujuan Zhao

Minghui Xia

Zhengxin Peng

Qiuyang Du

Yang Liu

Yu Xia

Panjing Lv

Xiao Zhang

Shijie Yuan

Xiaorong Xie

Jing Wang

Shuguo Sun

Xiang-Ping Yang

Ran He

Affiliations

Soon will be listed here.

Abstract

Intermittent fasting (IF) has been shown to ameliorate inflammation including DSS-induced colitis. It is well known that autophagy can limit inflammation and TFEB is a master transcriptional factor that regulates the processes of autophagy. However, whether TFEB is involved in the regulation of IF-mediated amelioration of inflammation and its mechanism remained unclear. In this study, we found that IF ameliorated DSS-induced colitis and induced TFEB. Nutrition deprivation induced TFEB puncta formation, which processes the characteristics of liquid-liquid phase separation (LLPS) showed by fluorescence recovery after photobleaching (FRAP) assay and 1,6-hexanediol treatment. We found the 24-33 amino acids of Coiled-Coil (CC) domain located in N terminus is essential for TFEB phase separation. Deletion of 24-33 amino acids within the CC domain inhibited TFEB-mediated target gene expression. In addition, we found transcription co-activators, EP300 and MED1, co-localized with TFEB condensate to formed a transcriptional hub that promotes the efficient expression of target genes. More importantly, TFEB inhibitor with ability to suppress TFEB puncta formation abolished the IF-mediated amelioration of DSS colitis. Together, these findings revealed a critical role of TFEB phase separation in the regulation of its transcriptional activity and anti-inflammatory functions induced by IF.

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