Ubiquitin-Specific Peptidase 10 Protects Against Hepatic Ischaemic/Reperfusion Injury via TAK1 Signalling

Abstract

Ubiquitin-specific peptidase 10 (USP10) protein is a deubiquitination enzyme involved in many important biological processes. However, the function of USP10 in hepatic ischaemic/reperfusion (I/R) injury remains unknown. The aim of this study was to explore the role of USP10 in hepatic I/R injury. USP10 Heterozygote mice and primary hepatocytes were used to construct hepatic I/R models. The effect of USP10 on hepatic I/R injury was examined via pathological and molecular analyses. Our results indicated that USP10 was significantly downregulated in the livers of mice after hepatic I/R injury and in hepatocytes subjected to hypoxia/reoxygenation stimulation. USP10 Heterozygote mice exhibited exacerbated hepatic I/R injury, as evidenced by enhanced liver inflammation via the NF-κB signalling pathway and increased hepatocyte apoptosis. Additionally, USP10 overexpression inhibited hepatocyte inflammation and apoptosis in hepatic I/R injury in vitro and in vivo . Mechanistically, our study demonstrated that USP10 knockdown exerted its detrimental effects on hepatic I/R injury by inducing activation of the transforming growth factor β-activated kinase 1 (TAK1)-JNK/p38 signalling pathways. TAK1 was required for USP10 function in hepatic I/R injury as TAK1 inhibition abolished USP10 function in vitro . In conclusion, our study demonstrated that USP10 plays a protective role in hepatic I/R injury by inhibiting the activation of the TAK1-JNK/p38 signalling pathways. Modulation of USP10/TAK1 might be a promising strategy to prevent this pathological process.

N‐acetylgalactosaminyltransferase‐4 protects against hepatic ischemia/reperfusion injury by blocking apoptosis signal‐regulating kinase 1 N‐terminal dimerization

“…Notably, GALNT4 (124‐578) and the N‐terminal region of ASK1 (1‐678) mediated the direct interaction between these two proteins (Figure 6D). Because the N‐terminal coiled‐coil domain of ASK1 is significantly involved in its N‐terminal dimerization and its subsequent activation upon extracellular stress, [ 20 ] we then investigated whether ASK1 dimerization is regulated by GALNT4. Notably, the presence of GALNT4 dramatically inhibited ASK1 N‐terminal dimerization (Figure 6E).…”

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

“…In the ischemia-reperfusion model, USP10 -KO mice exhibited severe injury and inflammation. In this model, USP10 suppresses apoptosis by inhibiting TAK1 [ 89 , 90 ]. USP10 protects endometrial stromal cells from apoptosis and promotes cell proliferation by deubiquitinating Raf-1, which activates the Raf-1/MEK/ERK pathway.…”

Maternal Inflammation Exaggerates Offspring Susceptibility to Cerebral Ischemia–Reperfusion Injury via the COX-2/PGD2/DP2 Pathway Activation

“…Prostaglandin D2 (PGD2), one of the COX-2-mediated metabolites of arachidonic acid, exerts physiological effects through the D-type prostanoid receptor (DP 1 and DP 2 ) [ 33 – 35 ]. There is accumulating evidence that inflammatory response cascades are stimulated, leading to further apoptosis and necrosis of cells [ 36 ]. Inflammation and apoptosis are involved in the mechanisms of cerebral I/R injury [ 7 , 37 – 39 ].…”