hcv activates oxidative stress defense system and suppresses polyamine biosynthesis
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Engelhardt Institute of Molecular Biology Russian Academy of Sciences. HCV activates oxidative stress defense system and suppresses polyamine biosynthesis. Smirnova Olga. HCV induces oxidative stress: mechanisms and consequences. HCV-induced oxidative stress can contribute to: Liver fibrosis - PowerPoint PPT PresentationTRANSCRIPT
HCV activates oxidative stress defense system and suppresses
polyamine biosynthesis
Smirnova OlgaSmirnova Olga
Engelhardt Institute of Molecular BiologyRussian Academy of Sciences
HCV induces oxidative stress: mechanisms and HCV induces oxidative stress: mechanisms and consequencesconsequences
1.1. HCV-induced oxidative stress can contribute to:HCV-induced oxidative stress can contribute to:• Liver fibrosisLiver fibrosis• ““Non-Vogelstein type” cancerogenesisNon-Vogelstein type” cancerogenesis• Interferon Interferon resistance in chronic hepatitis C patients resistance in chronic hepatitis C patients• Insulin resistance Insulin resistance • Alteration of iron homeostasis Alteration of iron homeostasis viavia inhibition of hepcidin expression inhibition of hepcidin expression
2.2. HCV causes oxidative stress by multiple mechanisms:HCV causes oxidative stress by multiple mechanisms:• Core and NS5A proteins alter calcium homeostasis resulting in Core and NS5A proteins alter calcium homeostasis resulting in
accumulation of Reactive Oxygen Species (ROS)accumulation of Reactive Oxygen Species (ROS)• E1, E2, and NS4B proteins induce ER-stress which can also lead to E1, E2, and NS4B proteins induce ER-stress which can also lead to
activation of ER oxidoreductases and to accumulation of reactive oxygen activation of ER oxidoreductases and to accumulation of reactive oxygen species (ROS)species (ROS)
• HCV proteins activate NADPH oxidase 4 (Nox4) expressionHCV proteins activate NADPH oxidase 4 (Nox4) expression
ROS [ROS]* Nonhazardousproductsantioxidants
Phase II detoxyfying
enzymes
ARE Phase II enzymes
Nrf2 Keap1
kinases
р
РRE SSATSpermine/spermidineN1-acetyltransferase
Nrf2р
NS5ACapsidprotein
Nrf2
NS4В PERKER
stress
pcDNA3.1(+)
pGL3-promoter luciferase luciferase
pP-ARE pP-PRE
inhibitors
Regulation of antioxidant defense systemRegulation of antioxidant defense system
ARE (Antioxidant Response Element)
PRE(Polyamine Response Element)
HCV proteins induce oxidative stress HCV proteins induce oxidative stress
HCV proteins activate ARE-dependent protein HCV proteins activate ARE-dependent protein expressionexpression
Up-regulation of HO-1 and Nqo1 gene expression by HCV proteins
Impact of HCV proteins on ARE-dependent luciferase expression
HCV proteins activate ARE-dependent transcription by HCV proteins activate ARE-dependent transcription by ROS-dependent and –independent mechanismsROS-dependent and –independent mechanisms
PDTC (pyrrolidine dithiocarbamate) acts as ROS scavenger
HCV proteins induce ARE-luciferase expression via PKC in a HCV proteins induce ARE-luciferase expression via PKC in a ROS-dependent, and by PI3K and CK2 in a ROS-ROS-dependent, and by PI3K and CK2 in a ROS-
independent manner.independent manner.
Wo (Wortmannin) – PI3K inhibitor Ro (Ro31-8220) – PKC inhibitorDRB – CK2 inhibitor
Effect of protein kinase inhibitors and PDTC on HO-1/Nqo1
gene expression, and Nrf2 localization
ConclusionsConclusions
► HCV proteins induced strong up-regulation of antioxidant defense system that HCV proteins induced strong up-regulation of antioxidant defense system that might mitigate harmful effects of HCV-induced oxidative stress during acute might mitigate harmful effects of HCV-induced oxidative stress during acute stage of hepatitis Cstage of hepatitis C
► Core, E1, E2, NS4B, and NS5A activate Nrf2/ARE pathway through three Core, E1, E2, NS4B, and NS5A activate Nrf2/ARE pathway through three independent mechanismsindependent mechanisms
► All five proteins induced accumulation of reactive oxygen species (ROS) which All five proteins induced accumulation of reactive oxygen species (ROS) which activated protein kinaseactivated protein kinase CC
► Core and NS5A proteins induced ROS-independent activation of casein kinase Core and NS5A proteins induced ROS-independent activation of casein kinase 2 and phosphoinositide-3 kinase2 and phosphoinositide-3 kinase
► The effects of NS4B, E1, and E2 were presumably mediated The effects of NS4B, E1, and E2 were presumably mediated via via ROS-ROS-independent PERK pathwayindependent PERK pathway
AcknowledgementsAcknowledgements
Sergey Kochetkov lab (EIMB)Sergey Kochetkov lab (EIMB) Karolinska InstitutetKarolinska Institutet ((SwedenSweden))
Alex IvanovAlex Ivanov Maria Isaguliants Maria Isaguliants Olga IvanovaOlga Ivanova Alexey KhomutovAlexey Khomutov
A.I. Virtanen Institute (Finland)A.I. Virtanen Institute (Finland) Tuomo KeinänenTuomo Keinänen
Mervi HyvonenMervi Hyvonen
The project was supported byThe project was supported by::► Russian Foundation for Basic ResearchRussian Foundation for Basic Research► Grant of President of Russian FederationGrant of President of Russian Federation
THANK YOU FOR YOUR ATTENTIONTHANK YOU FOR YOUR ATTENTION