Modulating Lysine Crotonylation in Ulcerative Colitis Maintains Mitochondrial Homeostasis: Modulating Crotonylation...

Area of Science:

• Biochemistry
• Molecular Biology
• Gastroenterology

Background:

• Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited therapeutic options.
• Lysine crotonylation (KCr), a newly identified post-translational modification (PTM), influences protein function and cellular processes.
• The role of KCr in UC pathogenesis remains largely unexplored.

Purpose of the Study:

• To investigate the pathophysiological significance of KCr in UC.
• To identify KCr-associated proteins and pathways involved in UC.
• To explore KCr as a potential therapeutic target for UC.

Main Methods:

• Utilized PTM proteomics to analyze KCr alterations in a dextran sulfate sodium (DSS)-induced UC mouse model.
• Validated differentially crotonylated proteins using Western blot assays.
• Performed in vitro functional and mechanistic analyses, including gain-of-function and loss-of-function mutations at KCr sites.

Main Results:

• Identified significant alterations in KCr sites and protein levels in UC colon tissue.
• Differentially crotonylated proteins, including citrate synthetase (CS), were predominantly linked to the tricarboxylic acid (TCA) cycle and mitochondrial localization.
• KEGG pathway analysis revealed enrichment in TCA cycle-related pathways.

Conclusions:

• Increased KCr restricts inflammasome activation via mitophagy, promoting mitochondrial homeostasis in UC.
• KCr modulation helps reduce oxidative stress and inhibit apoptosis in the context of UC.
• Lysine crotonylation emerges as a promising therapeutic target for ulcerative colitis treatment.