Publisher Correction: A naturally occurring antiviral ribonucleotide encoded by the human genome

Abstract

Change history: In the HTML version of this Letter, Extended Data Fig. 4 incorrectly corresponded to Fig. 4 (the PDF version of the figure was correct). This has been corrected online.

Structural Insight into the Substrate Scope of Viperin and Viperin-like Enzymes from Three Domains of Life

“…In addition, a recent preprint shows that ddhCTP can efficiently terminate the template-directed RNA synthesis catalyzed by SARS-CoV-2 RdRp . However, ddhCTP does not inhibit the RdRp from all viruses (e.g., picorna viruses); thus, we underscore the likelihood that other mechanisms for viperin-mediated viral restriction likely exist, including targeted protein degradation, and modulation of host membrane properties. ,,,,,,,, …”

“…Mammalian viperins [virus-inhibitory protein, endoplasmic reticulum-associated, interferon (IFN)-inducible] are IFN-inducible innate immune proteins, ,, which inhibit and/or are involved in the replication of a remarkable range of viruses, including chikungunya virus, Bunyamwera virus, Dengue virus, , tick-borne encephalitis virus, influenza A virus, West Nile virus, , human cytomegalovirus, hepatitis C virus, Sindbis virus, Japanese encephalitis virus, HIV-1, and other DNA and RNA viruses. , In addition, viperin has been implicated in the restriction of the bacterial pathogens Shigella flexneri and Listeria monocytogenes in cells through a currently unknown mechanism . The viperin-associated restriction mechanisms employed against different viruses have been proposed to involve interactions between viperin and a wide range of viral and host proteins involved in diverse cellular functions, including metabolism, , signaling, iron–sulfur cluster formation, lipid raft perturbation, targeted protein degradation, and isoprenoid biosynthesis. ,, Two recent reviews have discussed these topics in depth. , Independent of its antiviral functions, viperin has also been demonstrated to play a physiological role in regulating thermogenesis and lipogenesis. , The breadth of these functions is not immediately suggestive of a common or shared mechanism for antiviral function.…”

“…As a member of the radical S -adenosyl- l -methionine (SAM) superfamily of metalloenzymes, viperin employs a [4Fe-4S] (FeS) cluster cofactor that binds and supports homolytic cleavage of SAM, yielding methionine and a 5′-deoxyadenosyl radical (5′-dA•). , The only member of the radical SAM (RS) superfamily that does not catalyze this reaction is the cobalamin-dependent RS methyltransferase TsrM involved in the biosynthesis of thiostrepton. , In most reactions catalyzed by RS enzymes, SAM is consumed during turnover, making it a co-substrate; , however, a few examples in which SAM is a true cofactor and regenerated at the end of each catalytic cycle exist. − Almost all RS enzymes utilize 5′-dA• to abstract a target hydrogen atom from the substrate, initiating radical-based rearrangements that lead to product formation. , We recently demonstrated that viperin uses SAM as a co-substrate and that the 5′-dA• acts directly on the substrate, cytidine triphosphate (CTP) . In our proposed mechanism, the 5′-dA• abstracts the hydrogen atom from the 4′ position of the CTP ribose, resulting in a 4′ radical (Figure , intermediate 1 → 2 ).…”

“… a Conversion of CTP to ddhCTP by mammalian viperins. ddhCTP then acts as a small molecule chain terminator against the RNA-dependent RNA-polymerases (RdRp) from multiple flaviviruses, inhibiting the replication of the viral genomes …”

Divergent Antiviral Mechanisms of Two Viperin Homeologs in a Recurrent Polyploid Fish

“…Viperin has been found to interact with a wide variety of host and viral proteins, and the complex network of interactions inhibits viral RNA transcription and replication (28)(29)(30), interrupts viral particle assembly and maturation (14), or impairs viral budding and release (20,31,32). Another way relies on the catalytic activity of Viperin to generate 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP), which can directly interfere with RNA synthesis and the replication of flaviviruses (33). Similar to mammal, fish viperin is considered an important antiviral gene because its expression is also induced by LPS, poly(I:C), or viruses (15,(34)(35)(36)(37)(38)(39)(40).…”