Elucidating Sepsis-Associated Liver Dysfunction from the Perspective of “Protein Quality Control”

August 31, 2026

TG2-Mediated Vimentin Cross-Linking Regulates Inflammation in Hepatic Macrophages

A research group at Gifu University, in collaboration with the RIKEN CSRS, The Jikei University School of Medicine, and Nagoya University, has identified a new molecular mechanism underlying the progression of sepsis-associated liver dysfunction (SALD).
Sepsis is a disease in which an excessive immune response to infection triggers systemic inflammation, leading to severe organ damage. The liver is particularly susceptible to the effects of sepsis, and once liver dysfunction develops, the mortality rate reaches approximately 60%. However, many aspects of the underlying mechanisms remain unclear, and no effective treatments have been established.

The research group discovered that in liver macrophages activated by the bacterial toxin lipopolysaccharide (LPS), the protein cross-linking enzyme “transglutaminase 2 (TG2)” cross-links the cytoskeletal protein “vimentin,” reorganizing it into a fibrous network that forms a “cage-like structure” around the nucleus. It was revealed that this structural change hinders the mobilization of proteasomes to protein aggregates, and by inhibiting the degradation of the inflammatory signaling molecule TRAF6, it causes inflammation to persist. On the other hand, inhibiting TG2 or vimentin activated a new protein degradation pathway mediated by Rab27a-positive vesicles, which promoted the degradation of TRAF6 and thereby suppressed inflammation. Furthermore, we confirmed that TG2 inhibition improved survival rates in a sepsis mouse model.

This study redefines sepsis-induced liver injury not merely as a “cytokine storm,” but as a disease characterized by the breakdown of protein quality control (proteostasis), and is expected to lead to the development of new therapeutic agents.

 

Original article

Science Advances　DOI: 10.1126/sciadv.aea7513

Y. Xu, T. Su, M. Hricha, N. Dohmae, T. Suzuki, Y. Sakamaki, H. Aoyagi, H. Aizaki, H. Nishimura, E. Furuhata, Y. Gong, Q. Cheng, B. Zhang, C. He, K. Yanaka, Y. Furutani, H. Tatsukawa, H. Suzuki, W. Yu, X.-Y. Qin,

"Transglutaminase 2 regulates vimentin-dependent proteostasis during macrophage activation".

Contact

Naoshi Dohmae
Unit Leader
Biomolecular Characterization Unit