HCV core protein uses multiple mechanisms to induce oxidative stress in human hepatoma huh7 cells

Alexander V. Ivanov, Olga A. Smirnova, Irina Y. Petrushanko, Olga N. Ivanova, Inna L. Karpenko, Ekaterina Alekseeva, Irina Sominskaya, Alexander A. Makarov, Birke Bartosch, Sergey N. Kochetkov, Maria G. Isaguliants

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

Abstract

Hepatitis C virus (HCV) infection is accompanied by the induction of oxidative stress, mediated by several virus proteins, the most prominent being the nucleocapsid protein (HCV core). Here, using the truncated forms of HCV core, we have delineated several mechanisms by which it induces the oxidative stress. The N-terminal 36 amino acids of HCV core induced TGFβ1-dependent expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4, both of which independently contributed to the production of reactive oxygen species (ROS). The same fragment also induced the expression of cyclo-oxygenase 2, which, however, made no input into ROS production. Amino acids 37–191 of HCV core up-regulated the transcription of a ROS generating enzyme cytochrome P450 2E1. Furthermore, the same fragment induced the expression of endoplasmic reticulum oxidoreductin 1α. The latter triggered efflux of Ca2+ from ER to mitochondria via mitochondrial Ca2+ uniporter, leading to generation of superoxide anions, and possibly also H2O2. Suppression of any of these pathways in cells expressing the full-length core protein led to a partial inhibition of ROS production. Thus, HCV core causes oxidative stress via several independent pathways, each mediated by a distinct region of the protein.

Original languageEnglish
Pages (from-to)2745-2770
Number of pages26
JournalViruses
Volume7
Issue number6
DOIs
Publication statusPublished - 29 May 2015

Keywords

  • Cytochrome P450
  • ER oxidoreductin
  • Hepatitis C virus
  • NADPH oxidase
  • Oxidative stress
  • Reactive oxygen species
  • Transforming growth factor

Field of Science

  • 3.1 Basic medicine
  • 3.3 Health sciences

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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