Viperin: A Radical SAM‐dependent Approach in the Regulation of Farnesylpyrophosphate Synthase

Abstract

Viperin is an endoplasmic-reticulum associated antiviral responsive protein, which is highly upregulated in eukaryotic cells upon viral infection through both interferon-dependent and -independent pathways. It is predicted to be a radical SAM (S-adenosyl-L-methionine) enzyme, but little is known regarding how, or if, viperin exploits radical SAM chemistry in exerting its antiviral activity. Viperin is reported to target various cellular and viral proteins, we therefore examined the inhibitory effects of viperin against one target - farnesyl pyrophosphate synthase (FPPS). FPPS is a key enzyme in cholesterol and isoprenoid biosynthesis, and thus, because numerous enveloped viruses utilize cholesterol-rich lipid rafts for viral budding from the host cell membrane, it is thought that viperin may retard viral budding by inhibiting FPPS. Consistent with this hypothesis, we demonstrated that transfection of viperin in human embryonic kidney cells reduces the expression levels of co-transfected FPPS. The native N-terminal amphipathic helix of viperin was shown to be crucial for its inhibitory activity against FPPS. Surprisingly, we found that mutations of important residues in the radical SAM domain did not abolish viperin's inhibitory activity against FPPS; indeed, some mutations potentiate viperin's activity. Although viperin reductively cleaved SAM in a slow uncoupled reaction, the rate of cleavage was not increased in the presence of FPPS. These data suggest that viperin does not act as a radical SAM enzyme in reducing FPPS levels. Support or Funding Information National Institute of Health and Department of Chemistry, University of Michigan, Ann Arbor, MI 48109 Inhibition of Farnesylpyrophosphate synthase (FPPS) by Viperin may lead to lipid raft dispersion and stalling of viral budding This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.