Abstract
Human APOBEC3G (hA3G) is a cytidine deaminase that restricts replication of certain viruses. We have previously reported that hA3G was a host restriction factor against hepatitis C virus (HCV) replication, and hA3G stabilizers showed a significant inhibitory activity against HCV. However, the molecular mechanism of hA3G against HCV remains unknown. We show in this study that hA3G’s C-terminal directly binds HCV non-structural protein NS3 at its C-terminus, which is responsible for NS3’s helicase and NTPase activity. Binding of hA3G to the C-terminus of NS3 reduced helicase activity, and therefore inhibited HCV replication. The anti-HCV mechanism of hA3G appeared to be independent of its deamination activity. Although early stage HCV infection resulted in an increase in host hA3G as an intracellular response against HCV replication, hA3G was gradually diminished after a long-term incubation, suggesting an unknown mechanism(s) that protects HCV NS3 from inactivation by hA3G. The process represents, at least partially, a cellular defensive mechanism against HCV and the action is mediated through a direct interaction between host hA3G and HCV NS3. We believe that understanding of the antiviral mechanism of hA3G against HCV might open an interesting avenue to explore hA3G stabilizers as a new class of anti-HCV agents.
Highlights
Human cellular protein apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide-like 3G is a cytidine deaminase that interrupts the life cycle of certain viruses [1, 2]
The interesting finding was that the hepatitis C virus (HCV) NS3 specific peptide fragment sequences KVPVAYAAQGYKV, KCGAVDLYLVTRN and KSIDFIPVETLDVVTRS were detected in the bands, suggesting that HCV NS3 was bound to Human APOBEC3G (hA3G)-HA
Interferon-alpha in combination with ribavirin was the standard treatment for chronic hepatitis C in the past few decades
Summary
Human cellular protein apolipoprotein B messenger RNA (mRNA)-editing enzyme catalytic polypeptide-like 3G (human APOBEC3G, or hA3G) is a cytidine deaminase that interrupts the life cycle of certain viruses [1, 2]. The defensive function of hA3G was discovered first in cells infected with human immunodeficiency virus type 1 (HIV-1) [3], and the antiviral mechanism of hA3G is mainly associated with induction of G/A hypermutation in HIV-1 genome [4, 5]. HIV-1 Vif binds hA3G in the cytoplasm, forming the Vif-Cul5-SCF complex which facilitates ubiquitination and subsequent degradation of hA3G by proteosomes [6]. Our previous report showed that hA3G is a cellular restriction factor against hepatitis C. Interaction between Human APOBEC3G and HCV NS3
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