Targeting the RNF31-TFEB-NLRP3 Axis With a Curcumin Analog to Restore Autophagy and Alleviate Intestinal Inflammation

Area of Science:

• Gastroenterology
• Molecular Biology
• Immunology

Background:

• Inflammatory bowel disease (IBD) involves impaired autophagy and chronic inflammation.
• The E3 ubiquitin ligase RNF31 is elevated in IBD, but its role is unclear.

Purpose of the Study:

• To elucidate the pathogenic mechanisms of RNF31 in IBD.
• To investigate the RNF31-TFEB interaction and its impact on autophagy and inflammation.
• To evaluate a novel curcumin analog (CM-C1) as a therapeutic agent targeting this pathway.

Main Methods:

• In vitro studies using LPS-stimulated cells to analyze TFEB phosphorylation, RNF31 interaction, ubiquitination, and localization.
• In vivo studies using a DSS-induced IBD mouse model.
• Assessment of intestinal pathology, inflammation, and key protein levels (RNF31, TFEB, NLRP3) after CM-C1 treatment.

Main Results:

• TFEB was identified as a novel substrate of RNF31.
• LPS stimulation led to TFEB phosphorylation, RNF31 binding, ubiquitination, degradation, suppressed autophagy, and NLRP3 inflammasome activation.
• CM-C1 disrupted the RNF31-TFEB interaction, promoting TFEB nuclear translocation, restoring autophagy, reducing inflammation, and improving gut microbiota.

Conclusions:

• The RNF31-TFEB-NLRP3 axis is a critical pathogenic pathway in IBD.
• CM-C1 effectively targets this axis, demonstrating potential as a multimodal therapeutic for IBD by restoring autophagy and alleviating inflammation.