Premium
Defining the role of SREBPs in Viral Infection
Author(s) -
York Autumn Gabrielle,
Bensinger Steven J
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.991.5
Subject(s) - sterol regulatory element binding protein , biology , lipid metabolism , fatty acid synthesis , transcription factor , biochemistry , fatty acid , gene
Over 180 million people are infected with Hepatitis C Virus (HCV). Chronic HCV infection can cause liver cirrhosis and cancer, and is the primary indication for liver transplant. To date, there is no vaccine and only limited treatment options for HCV. Several studies have noted alterations in host lipid metabolism in response to HCV infection. The S terol R egulatory E lement B inding P roteins (SREBPs) are the master transcriptional regulators of de novo lipid biosynthesis. SREBPs regulate upwards of 40 genes involved in lipid biosynthesis, lipoprotein import and intracellular transport, including the rate limiting enzymes in both cholesterol and fatty acid synthesis (HMG‐CoA Reductase and Acetyl‐CoA Carboxylase, respectively). Interestingly, many SREBP target genes are known to be upregulated in response to HCV infection. To better understand the importance of SREBP on HCV biology, we stably modified Huh 7.5.1 liver cells with shRNA against the 2 major isoforms of SREBPs (SREBP1 and 2) and SCAP, a chaperone protein required for SREBP activation (Loss‐of‐function SCAP acts as a double knockdown of SREBP1 and 2). Preliminary studies using immunofluorescence imaging and qPCR indicate significant attenuation of HCV lifecycle in response to loss‐of‐function SREBP1 and SREBP2. Markedly, loss‐of‐function SCAP attenuates HCV lifecycle to an even greater extent, suggesting that both SREBP1 and SREBP2 target genes are required for efficient HCV lifecycle. Conversely, gain‐of‐function of either SREBP1 or SREBP2 results in 20 to 30‐fold increase in viral replication, respectively. Our data provide strong evidence that SREBPs play a critical role in supporting HCV infection. In the future, we aim to define the mechanism by which SREBP and HCV interact on both a cellular and molecular level. Furthermore, our work will evaluate SREBP activation as a potential novel pharmacologic target for chronic HCV infection.