Transcript Mechanisms of regulation of oxidative stress by HCV Core

Mechanisms of regulation of oxidative stress
by HCV core protein
I. Karpenko, O. Smirnova, I. Petrashanko,
I. Alekseeva, I. Sominskaya, A. Makarov,
S. Kochetkov, A. Ivanov, M. Isaguliants
9th Annual Conference of the New Visby Network on Hepatitis C (HepC 2012)
HCV- induced oxidative stress is linked to
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Steatosis
Fibrosis, cirrhosis
Hepatocellular carcinoma
Alteration of iron homeostasis
HCV induces oxidative stress by multiple mechanisms
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Ca2+ efflux from the ER and mitochondrial decoupling
Induction of NAD(P)H oxidases 1 and 4 (Nox1 and Nox4)
Induction of ER stress
9th Annual Conference of the New Visby Network on Hepatitis C (HepC 2012)
Regulation of Nrf2/ARE pathway in HCV-infected cell
ROS
antioxidants
[ROS]
р― Nrf2 Keap1
Phase II enzymes
ARE
(Antioxidant Response Element)
kinases
NS5A
Capsid
protein
NS4В
ER
stress
Nonhazardous
products
PERK
ARE Phase II enzymes
9th Annual Conference of the New Visby Network on Hepatitis C (HepC 2012)
Previously we have shown that five HCV proteins activate
Nrf2/ARE pathway via distinct mechanisms
Core
E1
NS5A
E2
NS4B
ROS
PI3K
CK2
PKC
[PERK]
Nrf2
Mechanisms of
regulation of
oxidative stress
Phase II enzymes
Ivanov A.V. et. al. (2011),
PLOS One
ARE-dependent genes
9th Annual Conference of the New Visby Network on Hepatitis C (HepC 2012)
Panel of the truncated forms of the HCV core protein
1
191
1
Core (1-151)
151
Core (1-98)
98
1
1
Core (1-173)
173
1
1
1
36
60 37
173
191 (1-60)
Core
Core (1-36)
36
37
Core (1-191)
191
9th Annual Conference of the New Visby Network on Hepatitis C (HepC 2012)
Core (37-191)
Mechanisms of induction of oxidative stress by the core protein
1
36 37
O2*
173
191
O2*
ROS
H2O2
HyPer protein
(cytoplasmic)
Superoxide (O2*)
H2O2 sensor
9th Annual Conference of the New Visby Network on Hepatitis C (HepC 2012)
Mechanisms of activation of Nrf2/ARE pathway
1
36 37
173
O2*
O2*/H2O2
PI3K
CK2
PKC
Nrf2
Phase II enzymes
9th Annual Conference of the New Visby Network on Hepatitis C (HepC 2012)
191
Acknowledgements
Olga Smirnova
Dr. Ekaterina Alekseeva
Dr. Inna Karpenko
Dr. Irina Sominskaya
Dr. Irina Petrashanko
Prof. Alexander Makarov
Prof.Sergey Kochetkov
Dr. Alexander Ivanov
Prof. Maria Isaguliants
9th Annual Conference of the New Visby Network on Hepatitis C (HepC 2012)