Proteasome Activation by Hepatitis C Core Protein Is Reversed by Ethanol-Induced Oxidative Stress

Abstract

Background and Aims-The proteasome is a major cellular proteinase. Its activity is modulated by cellular oxidants. Hepatitis C core protein and ethanol exposure both cause enhanced oxidant generation. The aim was to investigate whether core protein, by its ability to generate oxidants, alters proteasome activity and whether these alterations are further affected byethanol exposure.

Ethanol Inhibits Antigen Presentation by Dendritic Cells

“…Previous studies suggested that ethanol does not alter phagocytosis or pinocytosis of exogenous antigens by DCs (1). However, Osna et al reported that ethanol inhibited proteasomal degradation of peptides and thus reduced their presentation by MHCI molecules in hepatocytes (26). To resolve these discordant observations and to further explore the possible inhibitory influence of ethanol on the processing of exogenous antigens taken up through an endocytic process as a potential mechanism for depressed Tcell activation, we compared the kinetics of endocytosed OVA protein degradation by DCs isolated from control and ethanolfed BALB/c mice.…”

“…There is a repertoire of distinct DC subsets (14) that are specialized to take up, process, and present exogenous and endogenous antigens to CD4 ϩ T cells via major histocompatibility complex class II (MHCII) molecules and to CD8 ϩ T cells by MHCI molecules, respectively (29). Recently, ethanol was shown to inhibit MHCI presentation of peptides by interfering with the proteasomal degradation of antigens in hepatocellular carcinoma cells in a CYP2E1-dependent manner (25,26). However, the influence of ethanol on antigen processing and presentation by DCs, along with the formation of the peptide-MHCII complex on the cell surface as it relates to impaired T-cell activation, has not been investigated previously.…”

Roles of the two distinct proteasome pathways in hepatitis C virus infection

“…This proteasome activation event is, however, reversed after ethanol exposure which considerably reduces proteasome function due to the induction of high oxidative stress [66] . Ethanol-elicited suppression of the proteasome in the liver ultimately results in a reduced generation of antigenic peptides and reduced MHC class Ⅰ-restricted antigen presentation on hepatocytes [68] .…”

“…In Huh-7 cells co-expressing the HCV core protein and CYP2E1, the core protein slightly enhances 20S proteasome activity through a direct interaction and via the induction of low CYP2E1-dependent oxidative stress [66,67] . This proteasome activation event is, however, reversed after ethanol exposure which considerably reduces proteasome function due to the induction of high oxidative stress [66] .…”

Ubiquitin-Proteasome Pathway, Alcohol and Hepatitis C Infection (HCV)

“…In addition, HCV proteins affect the enzyme activity: core protein regulate proteasome activity via protein-protein interactions and oxidative stress [8], while NS3 protein blocks the activity of IFNstimulated immunoproteasome (LMP7 subunit) that trims the peptides for antigen presentation in the context of MHC class I to cytotoxic T-lymphocytes [9].…”