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

Abstract

Background and Aims Ischemia‐reperfusion (I/R) injury is an inevitable complication of liver transplantation (LT) and compromises its prognosis. Glycosyltransferases have been recognized as promising targets for disease therapy, but their roles remain open for study in hepatic I/R (HIR) injury. Here, we aim to demonstrate the exact function and molecular mechanism of a glycosyltransferase, N‐acetylgalactosaminyltransferase‐4 (GALNT4), in HIR injury. Approach and Results By an RNA‐sequencing data‐based correlation analysis, we found a close correlation between GALNT4 expression and HIR‐related molecular events in a murine model. mRNA and protein expression of GALNT4 were markedly up‐regulated upon reperfusion surgery in both clinical samples from subjects who underwent LT and in a mouse model. We found that GALNT4 deficiency significantly exacerbated I/R‐induced liver damage, inflammation, and cell death, whereas GALNT4 overexpression led to the opposite phenotypes. Our in‐depth mechanistic exploration clarified that GALNT4 directly binds to apoptosis signal‐regulating kinase 1 (ASK1) to inhibit its N‐terminal dimerization and subsequent phosphorylation, leading to a robust inactivation of downstream c‐Jun N‐terminal kinase (JNK)/p38 and NF‐κB signaling. Intriguingly, the inhibitory capacity of GALNT4 on ASK1 activation is independent of its glycosyltransferase activity. Conclusions GALNT4 represents a promising therapeutic target for liver I/R injury and improves liver surgery prognosis by inactivating the ASK1‐JNK/p38 signaling pathway.

Inhibition of macrophage migration inhibitory factor (MIF) suppresses apoptosis signal-regulating kinase 1 to protect against liver ischemia/reperfusion injury

“…MAPK signaling has been recognized as the major molecular event contributing to hepatic I/R injury ( Imarisio et al, 2017 ; Wang et al, 2017 ). During the hepatic I/R process, damage-associated molecular patterns (DAMPs) and ROS stimulation of hepatocytes can activate JNK and p38 signals that result in cellular inflammation and apoptosis ( Yang et al, 2019 ; Zhou et al, 2021b ). Importantly, MIF has been reported to function in regulating MAPK signaling.…”

Lysosomal-associated transmembrane protein 5 deficiency exacerbates cerebral ischemia/reperfusion injury

“…Moreover, TOLLIP interacts with ASK1 to increase its N-terminal dimerization, exacerbating hepatic I/R injury by activating the downstream JNK/p38 signaling pathway ( Yan et al, 2019 ). On the contrary, N -acetylgalactosaminyltransferase-4 protects against hepatic I/R injury by inhibiting ASK1 N-terminal dimerization and inactivating the ASK1-JNK/p38 axis ( Zhou et al, 2021 ). In brain I/R, ASK1 undergoes phosphorylation and activation through NO-induced dimerization of ASK1, thereby activating the JNK pathway ( Liu et al, 2013 ).…”

Thioredoxin-interacting protein deficiency protects against severe acute pancreatitis by suppressing apoptosis signal-regulating kinase 1

“…Consistent with these results, we observed that TXNIP overexpression activated ASK1, leading to a significant increase in the phosphorylation levels of JNK and p38 proteins, whereas TXNIP knockout or downregulation showed the opposite trend. Studies have found that the binding of N-acetylgalactosaminyltransferase-4 to ASK1 inhibits its N-terminal dimerization and subsequent phosphorylation, thus leading to strong inactivation of downstream JNK/p38 signaling [ 60 ]. Moreover, the therapeutic use of ASK1 inhibitors has been extensively described in several reviews [ 61 – 63 ].…”