How the antiviral protein viperin works
Lipid droplets consist of a core of neutral lipids surrounded by an outer phospholipid monolayer and associated proteins. These organelles are thought to be generated when neutral lipids accumulate in the endoplasmic reticulum (ER) bilayer. Recently, lipid droplets have been shown to play a role in several cellular processes, including lipid storage, lipid trafficking, and protein storage and degradation. The importance of this organelle is underscored by the fact that lipid droplets have been linked to several metabolic diseases, most notably diabetes and obesity. Lipid droplets have also been shown to play a critical role in the replication of several pathogens. One of the most well characterized examples is hepatitis C virus (HCV).
Viperin is an interferon (IFN)-induced antiviral protein that is induced upon HCV infection and inhibits HCV replication. Like the HCV NS proteins, viperin has been shown to localize to the cytosolic face of the ER through an N-terminal amphipathic alpha-helix. This N-terminal amphipathic alpha-helix is essential for viperin to inhibit HCV and influenza, as mutants lacking this domain have greatly reduced antiviral activity. Although the precise mechanism by which viperin inhibits HCV is still unknown, viperin was previously shown to inhibit influenza virus budding by disrupting plasma membrane lipid raft microdomains, which are sites of influenza virion assembly and budding. Independent of viral infection, the N-terminal amphipathic alpha-helix of viperin inhibits protein secretion and appears to induce ER membrane curvature.
Numerous questions remain about how lipid droplets are generated and used by viruses. This paper shows that the IFN-induced antiviral protein viperin, which localizes to the cytosolic face of the ER and inhibits HCV, localizes to lipid droplets. This paper shows that the N-terminal amphipathic alpha-helix of viperin that is responsible for ER localization is also necessary and sufficient to localize both viperin and the fluorescent protein dsRed to lipid droplets. Point mutations in the alpha-helix that prevent ER association also disrupt lipid droplet association, and sequential deletion mutants indicate that the same number of helical turns are necessary for ER and lipid droplet association. The N-terminal amphipathic alpha-helix of the hepatitis C viral protein NS5A can localize dsRed and viperin to lipid droplets. These findings indicate that the amphipathic alpha-helices of viperin and NS5A are lipid droplet-targeting domains and suggest that viperin inhibits HCV by localizing to lipid droplets using a domain and mechanism similar to that used by HCV itself.
Related:
- Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus. 2001 PNAS USA 98(26): 15125-15130
- Viroporins
- Hepatitis C Virus: a mountain to climb
- The Interferon Antiviral Response
Tags: Biology, HCV, interferon, Medicine, Microbiology, Science, Virology, virus
