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Published on: February 9, 2014
TRIM16 mediates YAP1 K63-linked ubiquitination to alleviate sepsis-induced acute liver injury through YAP/Nrf2 axis
Kaina Zhang1, Mengqing Liu1, Yeqing Zheng1
1Department of Pharmacology, School of Basic Medical Sciences, and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China.
Abstract:
Sepsis-induced liver injury is associated with high morbidity and mortality, yet its underlying mechanisms remain elucidated. In this study, we observed a significant reduction in the E3 ubiquitin ligase TRIM16 in lipopolysaccharide (LPS)-injured hepatocytes; however, its functional role and regulatory mechanisms were unclear. Using in vitro LPS-induced hepatocyte injury and in vivo cecal ligation and puncture (CLP)-induced septic liver injury models, we investigated TRIM16's effects via small interfering RNA and AAV9-overexpression plasmids in hepatocytes. Results demonstrated that TRIM16 overexpression rescued LPS-induced suppression of hepatocyte viability, reduced cellular dysfunction (ALT, AST), and significantly suppressed pro-inflammatory cytokine expression (TNF-α, IL-6) and oxidative stress (SOD, MDA). Conversely, TRIM16 silencing exacerbated hepatocyte damage and dysfunction. In septic mice, TRIM16 overexpression alleviated liver injury and fibrosis by inhibiting oxidative stress and inflammatory responses. Mechanistically, TRIM16 directly bound to and stabilized YAP1 through K63-linked ubiquitination, facilitating its nuclear translocation. This process enhanced Nrf2 activation and subsequent expression of antioxidant genes. Collectively, our findings reveal that TRIM16 protects against septic liver injury by mitigating oxidative stress and inflammation via the YAP1/Nrf2 pathway, highlighting its potential as a therapeutic target for sepsis-induced acute liver injury.
Insights
The E3 ubiquitin ligase TRIM16 protects against sepsis-induced liver injury by reducing inflammation and oxidative stress. TRIM16 stabilizes YAP1, activating the Nrf2 pathway to enhance antioxidant gene expression.
Area of Science:
- Biochemistry
- Cell Biology
- Immunology
Background:
- Sepsis-induced liver injury presents a significant clinical challenge with high mortality rates.
- The precise molecular mechanisms underlying sepsis-induced liver injury are not fully understood.
- The role of the E3 ubiquitin ligase TRIM16 in this context was previously unclear.
Purpose of the Study:
- To investigate the functional role of TRIM16 in lipopolysaccharide (LPS)-induced and sepsis-induced liver injury.
- To elucidate the molecular mechanisms by which TRIM16 exerts its protective effects.
- To evaluate TRIM16 as a potential therapeutic target for sepsis-induced acute liver injury.
Main Methods:
- In vitro studies utilized lipopolysaccharide (LPS)-induced hepatocyte injury models.
- In vivo studies employed cecal ligation and puncture (CLP)-induced septic liver injury models in mice.
- TRIM16 function was modulated using small interfering RNA (siRNA) and adeno-associated virus serotype 9 (AAV9)-overexpression plasmids.
Main Results:
- TRIM16 overexpression improved hepatocyte viability and reduced liver dysfunction markers (ALT, AST) in LPS-injured cells.
- TRIM16 suppressed pro-inflammatory cytokines (TNF-α, IL-6) and oxidative stress markers (SOD, MDA).
- TRIM16 overexpression alleviated liver injury and fibrosis in septic mice by inhibiting inflammation and oxidative stress.
- Mechanistically, TRIM16 stabilized YAP1 via K63-linked ubiquitination, promoting its nuclear translocation and subsequent Nrf2 activation.
Conclusions:
- TRIM16 plays a crucial protective role against sepsis-induced liver injury.
- TRIM16 mitigates liver damage by suppressing oxidative stress and inflammation through the YAP1/Nrf2 pathway.
- TRIM16 represents a promising therapeutic target for managing sepsis-induced acute liver injury.
