All-trans retinoic acid inhibits HCV replication by downregulating core levels via E6AP-mediated proteasomal degradation

Here, we found that all -trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, strengthens the anti-viral defense mechanism of E6-associated protein (E6AP) that downregulates hepatitis C virus (HCV) Core levels via ubiquitin-dependent proteasomal degradation. For this effect, ATRA downregulated both protein and enzyme activity levels of DNA methyltransferase 1 and 3b and activated E6AP expression via promoter hypomethylation in HepG2 cells but not in Hep3B cells, in which p53 was absent. Ectopic p53 expression but not E6AP overexpression restored the ability of ATRA to downregulate HCV Core levels in Hep3B cells, suggesting a direct role of p53 in the E6AP-mediated ubiquitination of HCV Core. ATRA also downregulated HCV Core levels during HCV infection in Huh7D cells to inhibit virus replication, providing theoretical basis for the clinical application of ATRA against HCV infection. (c) 2022 Elsevier Inc. All rights reserved.

Automated summary

This study demonstrates that all-trans retinoic acid (ATRA) enhances the anti-viral defense mechanism of E6-associated protein (E6AP) and downregulates hepatitis C virus (HCV) Core levels via ubiquitin-dependent proteasomal degradation. ATRA affects the function of HepG2 cells by regulating DNA methyltransferase and promoter hypomethylation, and p53 plays a direct role in the E6AP-mediated ubiquitination of HCV Core. Additionally, ATRA inhibits virus replication by reducing HCV Core levels during HCV infection.