A naturally occurring antiviral ribonucleotide encoded by the human genome

Anthony S. Gizzi, Tyler L. Grove, Jamie Jon Arnold, Joyce Jose, Rohit K. Jangra, Scott J. Garforth, Quan Du, Sean M. Cahill, Natalya G. Dulyaninova, James D. Love, Kartik Chandran, Anne R. Bresnick, Craig Eugene Cameron, Steven C. Almo

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Viral infections continue to represent major challenges to public health, and an enhanced mechanistic understanding of the processes that contribute to viral life cycles is necessary for the development of new therapeutic strategies 1 . Viperin, a member of the radical S-adenosyl-l-methionine (SAM) superfamily of enzymes, is an interferon-inducible protein implicated in the inhibition of replication of a broad range of RNA and DNA viruses, including dengue virus, West Nile virus, hepatitis C virus, influenza A virus, rabies virus 2 and HIV 3,4 . Viperin has been suggested to elicit these broad antiviral activities through interactions with a large number of functionally unrelated host and viral proteins 3,4 . Here we demonstrate that viperin catalyses the conversion of cytidine triphosphate (CTP) to 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP), a previously undescribed biologically relevant molecule, via a SAM-dependent radical mechanism. We show that mammalian cells expressing viperin and macrophages stimulated with IFNα produce substantial quantities of ddhCTP. We also establish that ddhCTP acts as a chain terminator for the RNA-dependent RNA polymerases from multiple members of the Flavivirus genus, and show that ddhCTP directly inhibits replication of Zika virus in vivo. These findings suggest a partially unifying mechanism for the broad antiviral effects of viperin that is based on the intrinsic enzymatic properties of the protein and involves the generation of a naturally occurring replication-chain terminator encoded by mammalian genomes.

Original languageEnglish (US)
Pages (from-to)610-614
Number of pages5
JournalNature
Volume558
Issue number7711
DOIs
StatePublished - Jun 28 2018

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Ribonucleotides
Cytidine Triphosphate
Human Genome
Antiviral Agents
Methionine
RNA Replicase
Flavivirus
Rabies virus
West Nile virus
Dengue Virus
HIV-2
DNA Viruses
RNA Viruses
Influenza A virus
Viral Proteins
Virus Diseases
Life Cycle Stages
Hepacivirus
Interferons
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Gizzi, A. S., Grove, T. L., Arnold, J. J., Jose, J., Jangra, R. K., Garforth, S. J., ... Almo, S. C. (2018). A naturally occurring antiviral ribonucleotide encoded by the human genome. Nature, 558(7711), 610-614. https://doi.org/10.1038/s41586-018-0238-4
Gizzi, Anthony S. ; Grove, Tyler L. ; Arnold, Jamie Jon ; Jose, Joyce ; Jangra, Rohit K. ; Garforth, Scott J. ; Du, Quan ; Cahill, Sean M. ; Dulyaninova, Natalya G. ; Love, James D. ; Chandran, Kartik ; Bresnick, Anne R. ; Cameron, Craig Eugene ; Almo, Steven C. / A naturally occurring antiviral ribonucleotide encoded by the human genome. In: Nature. 2018 ; Vol. 558, No. 7711. pp. 610-614.
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Gizzi, AS, Grove, TL, Arnold, JJ, Jose, J, Jangra, RK, Garforth, SJ, Du, Q, Cahill, SM, Dulyaninova, NG, Love, JD, Chandran, K, Bresnick, AR, Cameron, CE & Almo, SC 2018, 'A naturally occurring antiviral ribonucleotide encoded by the human genome', Nature, vol. 558, no. 7711, pp. 610-614. https://doi.org/10.1038/s41586-018-0238-4

A naturally occurring antiviral ribonucleotide encoded by the human genome. / Gizzi, Anthony S.; Grove, Tyler L.; Arnold, Jamie Jon; Jose, Joyce; Jangra, Rohit K.; Garforth, Scott J.; Du, Quan; Cahill, Sean M.; Dulyaninova, Natalya G.; Love, James D.; Chandran, Kartik; Bresnick, Anne R.; Cameron, Craig Eugene; Almo, Steven C.

In: Nature, Vol. 558, No. 7711, 28.06.2018, p. 610-614.

Research output: Contribution to journalArticle

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T1 - A naturally occurring antiviral ribonucleotide encoded by the human genome

AU - Gizzi, Anthony S.

AU - Grove, Tyler L.

AU - Arnold, Jamie Jon

AU - Jose, Joyce

AU - Jangra, Rohit K.

AU - Garforth, Scott J.

AU - Du, Quan

AU - Cahill, Sean M.

AU - Dulyaninova, Natalya G.

AU - Love, James D.

AU - Chandran, Kartik

AU - Bresnick, Anne R.

AU - Cameron, Craig Eugene

AU - Almo, Steven C.

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N2 - Viral infections continue to represent major challenges to public health, and an enhanced mechanistic understanding of the processes that contribute to viral life cycles is necessary for the development of new therapeutic strategies 1 . Viperin, a member of the radical S-adenosyl-l-methionine (SAM) superfamily of enzymes, is an interferon-inducible protein implicated in the inhibition of replication of a broad range of RNA and DNA viruses, including dengue virus, West Nile virus, hepatitis C virus, influenza A virus, rabies virus 2 and HIV 3,4 . Viperin has been suggested to elicit these broad antiviral activities through interactions with a large number of functionally unrelated host and viral proteins 3,4 . Here we demonstrate that viperin catalyses the conversion of cytidine triphosphate (CTP) to 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP), a previously undescribed biologically relevant molecule, via a SAM-dependent radical mechanism. We show that mammalian cells expressing viperin and macrophages stimulated with IFNα produce substantial quantities of ddhCTP. We also establish that ddhCTP acts as a chain terminator for the RNA-dependent RNA polymerases from multiple members of the Flavivirus genus, and show that ddhCTP directly inhibits replication of Zika virus in vivo. These findings suggest a partially unifying mechanism for the broad antiviral effects of viperin that is based on the intrinsic enzymatic properties of the protein and involves the generation of a naturally occurring replication-chain terminator encoded by mammalian genomes.

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Gizzi AS, Grove TL, Arnold JJ, Jose J, Jangra RK, Garforth SJ et al. A naturally occurring antiviral ribonucleotide encoded by the human genome. Nature. 2018 Jun 28;558(7711):610-614. https://doi.org/10.1038/s41586-018-0238-4