Viperin

Contributors: Marian Dominguez-Mirazo, Heloïse Georjon

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 () .  

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 () . 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 () .

Molecular mechanism

Fig.1: Catalytic activity of human Viperin generates ddhCTP ()

Viperins are members of the radical S-adenosylmethionine (rSAM) superfamily. This group of enzymes uses a 4Fe-4S] cluster to cleave S-adenosylmethionine (SAM) reductively, generating a radical that 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) ()

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 () .

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 (, ) .

Example of genomic structure

The Viperin is composed of 1 protein: pVip.

Here is an example found in the RefSeq database:

The Viperin system in Vibrio sp. SCSIO 43009 (GCF_023716525.1, NZ_CP071842) is composed of 1 protein: pVip (WP_182016311.1)

Distribution of the system among prokaryotes

Among the 22,803 complete genomes of RefSeq, the Viperin is detected in 118 genomes (0.52 %).

The system was detected in 95 different species.

Proportion of genome encoding the Viperin system for the 14 phyla with more than 50 genomes in the RefSeq database.

Structure

Viperin

Example 1

Experimental validation

      
graph LR;
    Bernheim_2020[Bernheim et al., 2020] --> Origin_0
    Origin_0[ pVip6
Selenomonas ruminatium 
2624749465] --> Expressed_0[Escherichia coli]
    Expressed_0[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_1
    Origin_1[ pVip7
Fibrobacter sp. UWT3 
2739066738] --> Expressed_1[Escherichia coli]
    Expressed_1[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_2
    Origin_2[ pVip9
Vibrio porteresiae 
2574301464] --> Expressed_2[Escherichia coli]
    Expressed_2[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_3
    Origin_3[ pVip12
Ruegeria intermedia 
2698137626] --> Expressed_3[Escherichia coli]
    Expressed_3[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_4
    Origin_4[ pVip15
Coraliomargarita akajimensis 
646713396] --> Expressed_4[Escherichia coli]
    Expressed_4[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_5
    Origin_5[ pVip21
Lewinella persica 
2515428782] --> Expressed_5[Escherichia coli]
    Expressed_5[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_6
    Origin_6[ pVip32
Phormidium sp. OSCR GFM 
2609132705] --> Expressed_6[Escherichia coli]
    Expressed_6[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_7
    Origin_7[ pVip34
Cryomorphaceae bacterium 
2619892213] --> Expressed_7[Escherichia coli]
    Expressed_7[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_8
    Origin_8[ pVip37
Shewanella sp. cp20 
2632937107] --> Expressed_8[Escherichia coli]
    Expressed_8[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_9
    Origin_9[ pVip39
Burkholderiales-76 UID4002 
2634960437] --> Expressed_9[Escherichia coli]
    Expressed_9[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_10
    Origin_10[ pVip44
Chondromyces crocatus 
2648875132] --> Expressed_10[Escherichia coli]
    Expressed_10[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_11
    Origin_11[ pVip46
Photobacterium swingsii 
2649993803] --> Expressed_11[Escherichia coli]
    Expressed_11[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_12
    Origin_12[ pVip57
Flavobacterium lacus 
2718503187] --> Expressed_12[Escherichia coli]
    Expressed_12[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_13
    Origin_13[ pVip58
Pseudoalteromonas ulvae 
2721736750] --> Expressed_13[Escherichia coli]
    Expressed_13[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_14
    Origin_14[ pVip60
Lacinutrix sp. JCM 13824 
2733913669] --> Expressed_14[Escherichia coli]
    Expressed_14[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_15
    Origin_15[ pVip61
Euryarchaeota archaeon SCGC AG-487_M08 
2741341560] --> Expressed_15[Escherichia coli]
    Expressed_15[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_16
    Origin_16[ pVip62
Fibrobacteria bacterium 
2743907592] --> Expressed_16[Escherichia coli]
    Expressed_16[Escherichia coli] ----> T7
    Bernheim_2020[Bernheim et al., 2020] --> Origin_17
    Origin_17[ pVip63
Pseudoalteromonas sp. XI10 
2744633848] --> Expressed_17[Escherichia coli]
    Expressed_17[Escherichia coli] ----> T7
    subgraph Title1[Reference]
        Bernheim_2020
end
    subgraph Title2[System origin]
        Origin_0
        Origin_1
        Origin_2
        Origin_3
        Origin_4
        Origin_5
        Origin_6
        Origin_7
        Origin_8
        Origin_9
        Origin_10
        Origin_11
        Origin_12
        Origin_13
        Origin_14
        Origin_15
        Origin_16
        Origin_17
end
    subgraph Title3[Expression species]
        Expressed_0
        Expressed_1
        Expressed_2
        Expressed_3
        Expressed_4
        Expressed_5
        Expressed_6
        Expressed_7
        Expressed_8
        Expressed_9
        Expressed_10
        Expressed_11
        Expressed_12
        Expressed_13
        Expressed_14
        Expressed_15
        Expressed_16
        Expressed_17
end
    subgraph Title4[Protects against]
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
        T7
end
    style Title1 fill:none,stroke:none,stroke-width:none
    style Title2 fill:none,stroke:none,stroke-width:none
    style Title3 fill:none,stroke:none,stroke-width:none
    style Title4 fill:none,stroke:none,stroke-width:none

    

References

10.1038/s41586-020-2762-2
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10.1146/annurev-virology-011720-095930
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10.1038/s41467-022-30269-9
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10.1002/1873-3468.13778
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10.1038/s41586-018-0238-4
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