The RSAD2 gene encodes the virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible (Viperin), also known as RSAD2 (radical SAM domain-containing 2). Viperin is an interferon-stimulated gene that functions as a multifunctional protein in viral activities. Viperin can be produced by either IFN-dependent or IFN-independent routes, and certain viruses may employ viperin to improve their infectivity.


Viperin is an interferon-stimulated gene whose expression inhibits many DNA and RNA viruses including CHIKVHCMVHCVDENVWNVSINVinfluenza, and HIV. Initially identified as an IFN-γ induced antiviral protein in human cytomegalovirus (HCMV) infected macrophages, it was reported that viperin could be induced by HCMV glycoprotein B in fibroblasts, but inhibits HCMV viral infection and down-regulates viral structural proteins. The reason why virus protein would induce viperin against itself is still not clear; however, the viral induced redistribution of viperin may reflect the mechanism of virus evading its antiviral activities. Viperin may also be induced and interact with HCMV viral proteins and relocate to mitochondria in HCMV viral infected cells to enhance viral infectivity by disrupting cellular metabolism.

Viperin is a radical SAM enzyme which is capable of producing the chain terminator ddhCTP (3ʹ-deoxy-3′,4ʹdidehydro-CTP), which inhibits the viral RNA dependent RNA polymerase (RdRp). This activity appears to abolish metabolism of amino acids and mitochondrial respiration.

In the inhibition of influenza virus budding and release, viperin is suggested to disrupt the lipid rafts on the cell’s plasma membrane by binding to and decreasing the enzyme activities of farnesyl diphosphate synthase (FPPS), an essential enzyme in isoprenoid biosynthesis pathway. Viperin was suggested to inhibit the viral replication of HCV via its interaction with host protein hVAP-33 and NS5A and disrupting the formation of the replication complex.


Human viperin is a single polypeptide of 361 amino acids with a predicted molecular weight of 42 kDa. The N-terminal 42 amino acids of viperin forms amphipathic alpha-helix, which is relatively less conserved in different species and has a minor effect on the antiviral activity of viperin. The N-terminal domain of viperin is required for its localization to the ER and lipid droplets. Amino acids 77-209 of viperin constitute the radical S-adenosyl methionine (SAM) domain, containing four conserved motifs. Motif 1 has three conserved cysteine residues, CxxCxxC, which is the Fe-S binding motif and also essential for antiviral activity. The C-terminal 218-361 amino acids of viperin are highly conserved in different species and essential for viperin dimerization. The C-terminal tail appears to be critical for the antiviral activities against HCV since a C-terminal flag tagged of viperin lost its antiviral activity.

When viperin is bound to SAM and Cytidine triphosphate (CTP) or uridine triphosphate (UTP) is used as a substrate, different kinetic parameters are achieved. It is predicted that the CTP substrate binds much more tightly with viperin because of the low Km value of the substrate. However, the overall structure of both UTP- and CTP-bound compounds are similar. The difference being that the uracil moiety is less effective then the cytosine moiety at binding and ordering turns A and B. Nucleotide-free viperin contains a (βα)6 partial barrel and has a disordered N-terminal extension and a partially ordered C-terminal extension. When the C-terminal tail is ordered, a six-residue α-helix, an eight-residue P-loop (that binds the γ-phosphate of CTP), and a 310-helix are revealed.

Cellular localization

Viperin is normally localized to the endoplasmic reticulum (ER) via its N-terminal domain, and also localized to lipid droplet, which are derived from the ER. However, it is also found in mitochondria in the HCMV infected fibroblasts.

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