# Hepatitis C Virus Core Induces p53 Ser-15 Phosphorylation to Facilitate E6-Associated Protein-Mediated Proteasomal Degradation of p53

## TL;DR

The hepatitis C virus Core protein manipulates p53 levels by promoting its degradation through a specific pathway, which may support viral replication and cancer development.

## Contribution

The study reveals a novel mechanism by which HCV Core uses E6AP to degrade phosphorylated p53, bypassing MDM2.

## Key findings

- HCV Core induces p53 phosphorylation at Ser-15, preventing MDM2-mediated degradation.
- Phosphorylated p53 is targeted for E6AP-mediated proteasomal degradation by HCV Core.
- E6AP's E3 ubiquitin ligase activity is essential for p53 degradation during HCV replication.

## Abstract

What are the main findings?
HCV Core upregulates p53 levels by inhibiting MDM2-mediated degradation of unphosphorylated p53.HCV Core downregulates p53 levels by targeting phosphorylated p53 for E6AP-mediated degradation.

HCV Core upregulates p53 levels by inhibiting MDM2-mediated degradation of unphosphorylated p53.

HCV Core downregulates p53 levels by targeting phosphorylated p53 for E6AP-mediated degradation.

What are the implications of the main findings?
HCV Core adopts the E6AP-mediated host protein degradation system to counteract the antiviral strategies of p53.HCV Core fine-tunes p53 levels that support cell survival, viral replication, and potentially oncogenesis in human hepatocytes.

HCV Core adopts the E6AP-mediated host protein degradation system to counteract the antiviral strategies of p53.

HCV Core fine-tunes p53 levels that support cell survival, viral replication, and potentially oncogenesis in human hepatocytes.

The hepatitis C virus (HCV) Core activates the ATM-Chk2 pathway, leading to phosphorylation of p53 at Ser-15, which inhibits mouse double minute 2 (MDM2)-mediated proteasomal degradation. This study reveals that HCV Core also promotes E6-associated protein (E6AP)-mediated degradation of p53 during HCV replication. In the presence of HCV Core, E6AP expression induced p53 ubiquitination, reduced its stability, and decreased p53 levels, whereas E6AP knockdown increased p53 levels. The E3 ubiquitin ligase activity of E6AP was critical for this process, as demonstrated using the E6AP C833A mutant and the E3 ligase inhibitor Heclin. Proteasomal inhibition with MG132 confirmed that HCV Core and E6AP act together to regulate p53 levels via the proteasome. Importantly, HCV Core-induced p53 phosphorylation was essential for E6AP-mediated degradation, as shown by the impairment of degradation in the presence of the ATM inhibitor KU-55933. E6AP also targeted p53 phosphorylated at Ser-15 by etoposide, as well as phosphomimetic mutants such as p53 S15D, but not non-phosphorylatable mutants such as p53 S15A. These findings suggest that HCV Core-induced p53 phosphorylation enhances E6AP-mediated degradation while preventing MDM2 from targeting p53, thereby maintaining p53 levels that support cell survival, viral replication, and potentially oncogenesis in human hepatocytes.