Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress
Authors: Aleem Siddiqui
Francesco Negro
Gulam Waris
Daniel Jeffery Felmlee
Journal: Journal of Virology (2007)
Discipline: MICROBIOLOGY
Keywords: Hepatic steatosis; chronic hepatitis C; HCV; gene expression; lipid metabolism
Affiliations: Department of Medicine, Division of Infectious Diseases, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA., Department of Medicine, Division of Infectious Diseases, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, Departments of Internal Medicine and Pathology and Immunology, University of Geneva Medical Center, 1 rue Michel-Servet, Geneva 1205, Switzerland

Abstract:  Hepatic steatosis is a common histological feature of chronic hepatitis C. Hepatitis C virus (HCV) gene expression has been shown to alter host cell cholesterol/lipid metabolism and thus induce hepatic steatosis. Since sterol regulatory element binding proteins (SREBPs) are major regulators of lipid metabolism, we sought to determine whether genotype 2a-based HCV infection induces the expression and posttranslational activation of SREBPs. HCV infection stimulates the expression of genes related to lipogenesis. HCV induces the proteolytic cleavage of SREBPs. HCV core and NS4b derived from genotype 3a are also individually capable of inducing the proteolytic processing of SREBPs. Further, we demonstrate that HCV stimulates the phosphorylation of SREBPs. Our studies show that HCV-induced oxidative stress and subsequent activation of the phosphatidylinositol 3-kinase (PI3-K)-Akt pathway and inactivation (phosphorylation) of PTEN (phosphatase and tensin homologue) mediate the transactivation of SREBPs. HCV-induced SREBP-1 and -2 activities were sensitive to antioxidant (pyrrolidine dithiocarbamate), Ca(2+) chelator 1,2-bis(aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-tetra(acetoxymethyl) ester (BAPTA-AM), and PI3-K inhibitor (LY294002). Collectively, these studies provide insight into the mechanisms of hepatic steatosis associated with HCV infection. 

Retracted: Yes

PubPeer comments:
 ![file] , 
 ![file] , 
 ![file] , 
 https: imgur.com 01Mw7bN , 
 Figure 1. https: imgur.com UQw3Fs4 , 
 2020 retraction. https: jvi.asm.org content 94 19 e01404-20 Volume 81, no. 15, p. 8122u20138130, 2007, https: doi.org 10.1128 JVI.00125-07. It has been called to our attention that the actin bands in Fig. 2A in Journal of Biological Chemistry 278:40778u201340787, 2003, https: doi.org 10.1074 jbc.M303248200 (article retracted), were reused in Fig. 1B and D and Fig. 2A and B. Figures 2A and B were constructed using their original blots. The different panels showing phosphorylation experiments with SREBP-1 and SREBP-2 suggest that these experiments were conducted independently and each panel was constructed from its independent original blots. However, the Flag-tagged SREBP-2 appears to be the same blot; this could be due to an unintentional error during assembling of the figures. We do not have the original blots to verify the blots, as these experiments were conducted more than 15 years ago. Given these circumstances, we retract this paper. ,