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Biomolecules 2014, 4(4), 885-896; doi:10.3390/biom4040885

Proteasome- and Ethanol-Dependent Regulation of HCV-Infection Pathogenesis

1
Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, 4101 Woolworth Ave, Omaha, NE 68105, USA
2
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
3
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
*
Author to whom correspondence should be addressed.
Received: 29 May 2014 / Revised: 5 August 2014 / Accepted: 16 September 2014 / Published: 29 September 2014
(This article belongs to the Special Issue Proteasomes and Its Regulators)
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Abstract

This paper reviews the role of the catabolism of HCV and signaling proteins in HCV protection and the involvement of ethanol in HCV-proteasome interactions. HCV specifically infects hepatocytes, and intracellularly expressed HCV proteins generate oxidative stress, which is further exacerbated by heavy drinking. The proteasome is the principal proteolytic system in cells, and its activity is sensitive to the level of cellular oxidative stress. Not only host proteins, but some HCV proteins are degraded by the proteasome, which, in turn, controls HCV propagation and is crucial for the elimination of the virus. Ubiquitylation of HCV proteins usually leads to the prevention of HCV propagation, while accumulation of undegraded viral proteins in the nuclear compartment exacerbates infection pathogenesis. Proteasome activity also regulates both innate and adaptive immunity in HCV-infected cells. In addition, the proteasome/immunoproteasome is activated by interferons, which also induce “early” and “late” interferon-sensitive genes (ISGs) with anti-viral properties. Cleaving viral proteins to peptides in professional immune antigen presenting cells and infected (“target”) hepatocytes that express the MHC class I-antigenic peptide complex, the proteasome regulates the clearance of infected hepatocytes by the immune system. Alcohol exposure prevents peptide cleavage by generating metabolites that impair proteasome activity, thereby providing escape mechanisms that interfere with efficient viral clearance to promote the persistence of HCV-infection. View Full-Text
Keywords: hepatitis C virus; proteasome; PA28; interferon-sensitive genes; ubiquitylation; antigen presentation; ethanol hepatitis C virus; proteasome; PA28; interferon-sensitive genes; ubiquitylation; antigen presentation; ethanol
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Osna, N.A.; Ganesan, M.; Donohue, T.M., Jr. Proteasome- and Ethanol-Dependent Regulation of HCV-Infection Pathogenesis. Biomolecules 2014, 4, 885-896.

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