NaCr promotes KCr to impede the inflammatory progression of ulcerative colitis. KCr induces mitophagy by activating the PINK1/PARKIN pathway to restrict NLRP3 inflammasome activation, thereby decreasing the production and release of various inflammatory cytokines, such as IL-1β and TNF-α. KCr induces mitophagy and inhibits NLRP3 inflammasome activation via the continuous activation of K375 site in citrate synthetase.
Abstract:
Ulcerative colitis (UC) is a chronic and persistent clinical condition that is challenging to cure. Lysine crotonylation (KCr), a recently discovered post-translational modification (PTM), alters protein structure, stability, localization and activity in a variety of processes including cell differentiation and organism development. This study was designed to elucidate the pathophysiological relevance of KCr in UC and uncover potential underlying mechanisms involved. PTM proteomics was employed to track dynamic alterations in KCr sites and protein level in the colon tissue of dextran sulfate sodium (DSS)-induced UC model mice. Following the validation of differentially crotonylated proteins via Western blot assay, functional and mechanistic analyses of specific KCr sites were conducted in vitro. Gain-of-function or loss-of-function mutations were implemented at selected protein KCr sites. The differentially crotonylated proteins including citrate synthetase (CS) between the colon tissue of DSS-induced mice and control mice were predominantly associated with the tricarboxylic acid (TCA) cycle, as evidenced by significant enrichment in the KEGG pathway analysis. These proteins were primarily localized in mitochondria, suggesting a potential link among UC pathogenesis, mitochondria and the TCA cycle. Collectively, increased KCr restricts inflammasome activation by inducing mitophagy, thereby maintaining mitochondrial homeostasis, reducing oxidative stress and inhibiting apoptosis in UC. KCr represents a potential promising therapeutic target for the treatment of UC.
Author list:
Tongtong Liu†, Binyan Lin†, Ying Zhang†, Jiayu Su, Xiaochao Hu, Xuan Wang, E-Hu Liu*, Shijia Liu*
How to cite:
T. Liu, B. Lin, Y. Zhang, J. Su, X. Hu, X. Wang, E.-H. Liu, S. Liu, Exploration 2025, 20240129.
https://doi.org/10.1002/EXP.20240129