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"HCV-Host Cell Interactions: ErbB3 binding protein 1 (Ebp1) as a modulator of HCV replication"

by
Priya Mishra
Molecular Biology, Genetics & Cancer Program
M.Sc., 2008, Patna University, India
B.Sc., 2005, T.M.B. University, India



Thesis Advisor: V.N. Pandey, Ph.D.
Associate Professor
Department of Microbiology, Biochemistry and Molecular Genetics

Thursday, August 4, 2016
11:30 A.M., International Center for Public Health (ICPH), 1st Floor auditorium


Abstract

Persistent Hepatitis C virus (HCV) infection leads to chronic hepatitis C (CHC), which often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). HCV utilizes or modulates the function of multiple host factors for establishing its persistent infection. We have recently identified a cellular factor ErbB3 binding protein 1 (Ebp-1), which specifically interacts with viral RNA genome and strongly inhibits HCV replication. We found that Ebp1 interacts with HCV proteins NS5A and NS5B, as well as host factor, protein kinase R (PKR). Ebp1 possesses two different isoforms, p48, and p42 resulting from differential splicing. We found that the longer isoform p48 that localizes in both the cytoplasm and the nucleus promotes HCV replication, whereas the shorter isoform p42 that exclusively resides in the cytoplasm, strongly inhibits HCV replication. Transient expression of individual isoforms in Ebp1-knockdown Huh7.5 cells confirmed that p48 and p42 isoforms, respectively, promote and inhibit HCV replication in Huh7.5 cells. We found that autophosphorylation of PKR was promoted by the p42 isoform while it was strongly inhibited by p48 isoform. The viral protein, NS5A, and p48-isoform have a synergistic effect on the inhibition of PKR autophosphorylation. Many viral RNAs activate PKR, which inhibits translation of viral protein via eIF-2 phosphorylation. Many other viruses have devised a mechanism to inhibit PKR and thus prevent inhibition of their protein synthesis. We propose that modulation of activation / autophosphorylation of PKR by p48 isoform together with NS5A may be an important mechanism devised by HCV to escape from innate antiviral immune responses by circumventing the p42-mediated inhibition of its replication.


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