Transglutaminase-mediated cytokeratin modifications implicated in bile-acid-induced hepatocyte death.

Authors

Hideki Tatsukawa, Haruka Nakagawa, Chin Mun Yee, Keiko Kuwata, Kiyotaka Hitomi

Published in

The FEBS journal. Oct 12, 2025. Epub Oct 12, 2025.

Abstract

Transglutaminases (TGs) are crosslinking enzymes that catalyze the formation of isopeptide bonds between glutamine and lysine residues. They consist of eight isozymes: TG1-TG7 and factor XIIIa. Our previous studies have shown that TG1 and TG2 facilitate hepatic apoptosis, contributing to liver fibrosis, and that their crosslinking substrates-cytokeratin 18 (K18) and cytokeratin 8 (K8)-are also targeted by TGs in a bile-duct-ligation-induced mouse model of liver fibrosis. However, the precise mechanisms by which TGs and keratins contribute to hepatocyte damage remain unclear. This study investigates the molecular mechanisms underlying TG1- and TG2-mediated cell death in hepatocytes exposed to bile acids. HepG2 cells and primary hepatocytes were treated with glycochenodeoxycholic acid (GCDCA), a toxic bile salt elevated in cholestasis. GCDCA-reduced cell viability and induced apoptosis in a dose-dependent manner. Knockdown of K18/K8 or TG1/TG2 by siRNA significantly attenuated GCDCA-induced apoptosis, indicating their contributory roles in hepatocyte injury. GCDCA-treated cells showed increased levels of proteins crosslinked by TG1 and TG2. In vivo analysis using cholestatic model mice also showed elevated high-molecular-weight protein complexes involving K18/K8, suggesting early-stage Mallory body formation, as observed in chronic liver injury. Mass spectrometry identified cytoskeletal proteins, such as vimentin and periplakin, and regulatory proteins, such as ATP synthase subunit β and PI3K adapter protein, as K18-crosslinked partners. These results suggest that TG1/TG2-mediated aggregation of K18 sequesters essential structural and survival proteins, promoting hepatocyte apoptosis. Targeting these pathological interactions may provide a novel therapeutic strategy to mitigate liver fibrosis and improve hepatocyte survival.

PMID:
41076566
Bibliographic data and abstract were imported from PubMed on 12 Oct 2025.

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