Abstract
Human guanylate-binding protein 1 (hGBP1) is an interferon-inducible protein involved in the host immune response against viral infection. In response to infection by influenza A virus (IAV), hGBP1 transcript and protein were significantly upregulated. Overexpression of hGBP1 inhibited IAV replication in a dose-dependent manner in vitro. The lysine residue at position 51 (K51) of hGBP1 was essential for inhibition of IAV replication. Mutation of K51 resulted in an hGBP1 that was unable to inhibit IAV replication. The viral nonstructural protein 1 (NS1) was found to interact directly with hGBP1. K51 of hGBP1 and a region between residues 123 and 144 in NS1 were demonstrated to be essential for the interaction between NS1 and hGBP1. Binding of NS1 to hGBP1 resulted in a significant reduction in both GTPase activity and the anti-IAV activity of hGBP1. These findings indicated that hGBP1 contributed to the host immune response against IAV replication and that hGBP1-mediated antiviral activity was antagonized by NS1 via binding to hGBP1.
Highlights
Influenza A virus (IAV) is single-stranded negative-sense segmented RNA virus that causes influenza in humans and many animal species [1,2]
We found that the Human guanylate-binding protein 1 (hGBP1) possessed antiviral activity against IAV replication and that this activity was antagonized by nonstructural protein 1 (NS1) via binding to hGBP1
A remarkable increase at hGBP1 protein level was detected in PR8-infected cells. These results showed that the expression of hGBP1 was significantly upregulated in response to IAV infection
Summary
Influenza A virus (IAV) is single-stranded negative-sense segmented RNA virus that causes influenza in humans and many animal species [1,2]. The IAV genome consists of 8 RNA segments that encode at least 11 known proteins such as hemagglutinin (HA), neuraminidase (NA), matrix protein 1 (M1), and nonstructural protein 1 (NS1). NS1 is an approximately 26 kDa protein comprising 228–237 amino acids depending on the viral strain. It is structurally divided into two distinct functional domains: an Nterminal RNA-binding domain (residues 1–73) and a C-terminal effector domain (residues 74–230). The C-terminal effector domain predominantly mediates interactions with a number of host cell proteins by which IAV antagonizes the host immune response, especially the limitation of interferon (IFN) production and the antiviral effects of IFN-induced proteins [3]. NS1 binds to dsRNA-activated antiviral protein kinase (PKR) to sequester the antiviral ability of PKR [5,6]
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