Abstract
Neddylation is a ubiquitin-like posttranslational modification that conjugates neural precursor cell expressed developmentally downregulated-8 (Nedd8) to specific substrates for regulation of protein activity. In light of current researches, the neddylation pathway is aberrant in the pathogenesis of many diseases. In our review, we summarize the versatile roles of neddylation in chronic liver diseases (CLDs). CLDs are one of the leading causes of chronic disease-associated deaths worldwide. There are diverse etiologic agents causing CLDs, mainly including hepatitis B virus (HBV) infection, nonalcoholic fatty liver disease (NAFLD), chronic exposure to alcohol or drugs, and autoimmune causes. So far, however, there remains a paucity of effective therapeutic approach to CLDs. In this review, we summarized the role of the neddylation pathway which runs through the chronic hepatitis B/NAFLD–liver fibrosis–cirrhosis–hepatocellular carcinoma (HCC) axis, a canonical pattern in the process of CLD development and progression. The dysregulation of neddylation may provide a better understanding of CLD pathology and even a novel therapeutic strategy. Correspondingly, inhibiting neddylation via MLN4924, a small molecule compound targeting NEDD8-activating enzyme (NAE), can potently alleviate CLD progression and improve the outcome. On this basis, profiling and characterization of the neddylation pathway can provide new insights into the CLD pathology as well as novel therapeutic strategies, independently of the etiology of CLD.
Highlights
Chronic liver disease (CLD) is posing a significant public health problem worldwide for it causes ∼2 million deaths annually
Chronic hepatitis/nonalcoholic fatty liver disease (NAFLD)–liver fibrosis–cirrhosis–hepatocellular carcinoma (HCC) axis is a canonical pattern in the process of CLD progression [124]
Recent studies in the neddylation pathway provides us with crucial clues that neddylation is a versatile pathway that takes on various aspects and phases of CLD (Table 3)
Summary
Chronic liver disease (CLD) is posing a significant public health problem worldwide for it causes ∼2 million deaths annually. Recent studies have uncovered that neddylation inhibition can repress HBV survival [64], alleviate steatosis [65], reduce liver fibrosis [66], and restrain pro-tumor inflammation [67]. Inhibits p73 transcriptional activity Inhibits NF-κB activity Inhibits NF-κB-mediated transcription Reduces E2F-1 stability Inhibits AICD-mediated transcriptional activation Increases protein stability Increases stability and nuclear localization Facilitates EGFR degradation Increases TGF-βRII stability Promotes Erk activation Inhibits apoptosis Suppresses caspase activity Activates DNA damage-induced ubiquitination Increase stability and nucleolar localization Increase RCAN1 stability via the proteasome pathway [75,76,77].
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