Viperin is an interferon-induced cellular protein that is conserved in animals. It has previously been shown to inhibit the replication of multiple viruses by producing the ribonucleotide 3'-deoxy-3',4'-didehydro (ddh)-cytidine triphosphate (ddhCTP), which acts as a chain terminator for viral RNA polymerase2. Here we show that eukaryotic viperin originated from a clade of bacterial and archaeal proteins that protect against phage infection. Prokaryotic viperins produce a set of modified ribonucleotides that include ddhCTP, ddh-guanosine triphosphate (ddhGTP) and ddh-uridine triphosphate (ddhUTP). We further show that prokaryotic viperins protect against T7 phage infection by inhibiting viral polymerase-dependent transcription, suggesting that it has an antiviral mechanism of action similar to that of animal viperin. Our results reveal a class of potential natural antiviral compounds produced by bacterial immune systems.
Sensor:Unknown
Activator:Direct
Activator:Direct binding
Effector:Nucleotide modifying
PFAM:PF04055, PF13353
contributors:
-Marian Dominguez-Mirazo
relevantAbstracts:
-doi:10.1038/s41586-020-2762-2
---
# Viperin
## Description
Viperins, for "Virus Inhibitory Protein, Endoplasmic Reticulum-associated, INterferon-inducible", are antiviral enzymes whose expression is stimulated by interferons in eukaryotic cells. They are important components of eukaryotic innate immunity, and present antiviral activity against a wide diversity of viruses, including double-stranded DNA viruses, single-strand RNA viruses and retroviruses (1).
Viperins, for "Virus Inhibitory Protein, Endoplasmic Reticulum-associated, INterferon-inducible", are antiviral enzymes whose expression is stimulated by interferons in eukaryotic cells. They are important components of eukaryotic innate immunity, and present antiviral activity against a wide diversity of viruses, including double-stranded DNA viruses, single-strand RNA viruses and retroviruses :ref{doi=10.1146/annurev-virology-011720-095930}.
Recently, Viperin-like enzymes were found in prokaryotes (pVips). Strikingly, like their eukaryotic counter-part with eukaryotic viruses, pVips provide clear protection against phage infection to their host, and therefore constitute a new defense system (2). Like eukaryotic Viperins, pVips produce modified nucleotides that block phage transcription, acting as chain terminators. They constitute a form of chemical defense. A recent study reported that pVips can be found in around 0.5% of prokaryotic genomes (3).
Recently, Viperin-like enzymes were found in prokaryotes (pVips). Strikingly, like their eukaryotic counter-part with eukaryotic viruses, pVips provide clear protection against phage infection to their host, and therefore constitute a new defense system :ref{doi=10.1038/s41586-020-2762-2}. Like eukaryotic Viperins, pVips produce modified nucleotides that block phage transcription, acting as chain terminators. They constitute a form of chemical defense. A recent study reported that pVips can be found in around 0.5% of prokaryotic genomes :ref{doi=10.1038/s41467-022-30269-9}.
Fig.1: Catalytic activity of human Viperin generates ddhCTP :ref{doi=10.1002/1873-3468.13778}
Fig.1: Catalytic activity of human Viperin generates ddhCTP (Ebrahimi et al. al., 2020)
Viperins are members of the radical S-adenosylmethionine (rSAM) superfamily. This group of enzymes use a [4Fe-4S] cluster to cleave S-adenosylmethionine (SAM) reductively, generating a radical which is generally transferred to a substrate. It was demonstrated that through their [4Fe-4S] cluster catalytic activity, eukaryotic viperins convert a ribonucleotide, the cytidine triphosphate (CTP) into a modified ribonucleotide, the 3'-deoxy-3',4'-didehydro-CTP (ddhCTP) (4,5).
Viperins are members of the radical S-adenosylmethionine (rSAM) superfamily. This group of enzymes use a [4Fe-4S] cluster to cleave S-adenosylmethionine (SAM) reductively, generating a radical which is generally transferred to a substrate. It was demonstrated that through their [4Fe-4S] cluster catalytic activity, eukaryotic viperins convert a ribonucleotide, the cytidine triphosphate (CTP) into a modified ribonucleotide, the 3'-deoxy-3',4'-didehydro-CTP (ddhCTP) :ref{doi=10.1038/s41586-018-0238-4}.
Prokaryotic Viperins also convert ribonucleotides triphosphate into modified ribonucleotides, but contrary to their eukaryotic counterparts can use a diversity of substrates to produce ddhCTP, or ddh-guanosine triphosphate (ddhGTP), or ddh-uridine triphosphate (ddhUTP), or several of these nucleotides for certain pVips (2).
Prokaryotic Viperins also convert ribonucleotides triphosphate into modified ribonucleotides, but contrary to their eukaryotic counterparts can use a diversity of substrates to produce ddhCTP, or ddh-guanosine triphosphate (ddhGTP), or ddh-uridine triphosphate (ddhUTP), or several of these nucleotides for certain pVips :ref{doi=10.1038/s41586-020-2762-2}.
Compared to the initial ribonucleotide triphosphate, the modified ddh-nucleotide product of Viperins lacks a hydroxyl group at the 3′ carbon of the ribose (Fig.1). The ddh-nucleotides produced by Viperins can be used as substrates by some viral RNA polymerases. Because of their lost hydroxyl group at the 3’carbon of the ribose, once incorporated into the newly forming viral RNA chain, these ddh-nucleotides act as chain terminators. By preventing further polymerization of the viral RNA chain, ddh-nucleotides can inhibit viral replication (2,4,5).
Compared to the initial ribonucleotide triphosphate, the modified ddh-nucleotide product of Viperins lacks a hydroxyl group at the 3′ carbon of the ribose (Fig.1). The ddh-nucleotides produced by Viperins can be used as substrates by some viral RNA polymerases. Because of their lost hydroxyl group at the 3’carbon of the ribose, once incorporated into the newly forming viral RNA chain, these ddh-nucleotides act as chain terminators. By preventing further polymerization of the viral RNA chain, ddh-nucleotides can inhibit viral replication :ref{doi=10.1038/s41586-020-2762-2,10.1038/s41586-018-0238-4}.
