Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity

Abstract

HCV induces oxidative stress but controls it tightly by inducing ROS scavengers. Among these, GPx4 plays an essential role in the HCV life cycle. Modulating oxidative stress in CHC by specifically targeting GPx4 may lower specific infectivity of virions and prevent hepatocarcinogenesis, especially in patients who remain difficult to be treated in the new era of interferon-free regimens.

Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

“…A similar calcium-mediated effect was recently observed for endogenous production of ROS as a result of the ER overload response in the HCV-infected cells [157]. Knock-down of GPx1 and GPx8, as well as of SOD1 or SOD2, in the infected cells had no significant impact on HCV replication [145, 154]. Another effect that ROS appear to have on HCV is an increase in HCV genome heterogeneity, which may contribute to the evolutional survival of the virus by ensuring viral escape from the immune system (during establishment of infection as well as during treatment) [158, 159].…”

“…We also observed the transcriptional and translational up-regulation of the expression of HO-1 and NAD(P)H:quinoneoxidoreductase 1 (Nqo1) in Huh7 cells overexpressing HCV core and NS5A proteins as well as their truncated variants [144]. Similarly, it has been shown that HCV infection leads to an enhanced expression of two classical Nrf2 target genes [27]: glutathione reductase ( in vitro ) and glutathione synthase ( in vivo ) [145]. On the other hand, for the acute infection in a cell culture system Blackam et al as well as Walters et al reported a down-regulation of a wide spectrum of antioxidant defense proteins such as catalase, Nqo1, and glutathione-metabolizing enzymes [146, 147].…”

“…The nonstructural proteins of HCV down-regulate expression of SOD1 and SOD2 and induce catalase, whereas HCV core enhances the expression of SOD2 [153]. Increased levels of sod2 mRNA are also observed in the HCVcc system [145], although no significant changes were reported in the catalase or dismutases levels in CHC patient livers [138]. HCV infection also increases the expression levels of GPx1 and GPx4 [145], implicated in protection against lipid peroxides.…”

“…Increased levels of sod2 mRNA are also observed in the HCVcc system [145], although no significant changes were reported in the catalase or dismutases levels in CHC patient livers [138]. HCV infection also increases the expression levels of GPx1 and GPx4 [145], implicated in protection against lipid peroxides. In addition, HCV NS3/4A protease was recently shown to cleave GPx8 [154].…”

Selenocysteine oxidation in glutathione peroxidase catalysis: an MS-supported quantum mechanics study

“…In the meantime, this enzyme (now GPx1) and homologs either working with selenium (SecGPx) or sulfur catalysis (CysGPx) [2] have been shown to fulfill metabolic roles far beyond the name-giving activity of the 'classical' glutathione peroxidase (GPx1), i. e. reduction of H 2 O 2 by glutathione (GSH) (compiled in [3]). Mammalian GPx1 also dampens insulin signaling [4] and NF-κB activation [5], mitochondrial GPx4 forms an essential sperm constituent [6][7][8], nuclear GPx4 contributes to chromatin compaction [9] and cytosolic GPx4 regulates NF-κB activation [10], 12/15-lipoxygenase-driven apoptosis [11] and ferroptosis [12,13], and increases hepatitis C virus infectivity [14]. GPx7, and likely GPx8, contribute to protein folding [15].…”