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RNA MODIFICATIONS

U-tail as a guardian against invading RNAs

Nature Structural & Molecular Biology volume 25, pages 903–905 (2018)Cite this article

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RNA uridylation offers a basis for diverse post-transcriptional regulation. Two recent studies reveal new roles of uridylation in immune defense against viruses and retrotransposons.

In an attempt to identify novel antiviral immunity genes, Le Pen et al.14 performed a forward genetic screen using Caenorhabditis elegans and its natural intestinal pathogen, the Orsay virus (OrV). The authors identified 16 worm isolates that were immune deficient against OrV, termed ovid mutants. Five isolates were defective in the RNA interference (RNAi) pathway, which is known to be important for antiviral defense16. In the nematode RNAi pathway, DRH-1, a homolog of RIG-I (a mammalian component of the interferon pathway), recognizes viral RNAs and interacts with Dicer (DCR-1) to generate virus-derived small interfering RNAs (viRNAs) that guide RNA silencing. One of the isolates (ovid-9), however, showed normal induction of viRNAs, implicating a novel and independent pathway. A causative nonsense mutation was found in the cde-1 gene, which encodes a 3′-terminal uridyltransferase, a distant homolog of mammalian TUT4 and TUT7. Moreover, an independently derived cde-1 knockout strain as well as a cde-1 catalytically dead mutant recapitulated the phenotype of high viral load, indicating that CDE-1-mediated 3′ uridylation counteracts viral infection. TAIL-seq and 3′ RACE-seq showed that CDE-1 indeed modifies the 3′ ends of viral RNAs without severely influencing the endogenous transcriptome. Depletion of mRNA decay enzymes such as those encoded by dis-3, exos-2 and xrn-2 led to accumulation of uridylated viral RNAs, indicating the contribution of these enzymes to the decay of uridylated viral RNAs. This is in line with previous studies showing that DIS3 degrades viral RNAs in fruit fly and in human cells17 and that uridylated mRNAs are removed by the exosome and decapping enzyme in human cells7. The authors further extended their work to ask whether uridylation also has a related function in influenza A virus (IAV) infection in mammalian cells. Indeed, the 3′ ends of IAV RNAs were highly uridylated in infected A549 human lung cells and mouse embryonic fibroblasts (MEFs). In Tut4 and Tut7 double-knockout MEFs, IAV mRNA uridylation was lost and IAV mRNAs accumulated. Taking these findings together, uridyltransferases modify and degrade viral RNAs to protect host cells in both invertebrates and vertebrates. In nematodes, the uridylation pathway acts in parallel with the RNAi pathway to fight RNA viruses, while in mammals it seems to complement the innate and adaptive immune responses. In the future, it will be necessary to uncover the exact contributions and the interplay between these different immune pathways.

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Fig. 1: Uridylation has diverse roles in RNA metabolism.
Fig. 2: Terminal uridyltransferases restrict viruses and retrotransposons.

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Authors and Affiliations

  1. Center for RNA Research, Institute for Basic Science, Seoul, Korea

    Jinah Yeo & V. Narry Kim

  2. School of Biological Sciences, Seoul National University, Seoul, Korea

    V. Narry Kim

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  1. Jinah Yeo
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  2. V. Narry Kim
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Correspondence to V. Narry Kim.

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Yeo, J., Kim, V.N. U-tail as a guardian against invading RNAs. Nat Struct Mol Biol 25, 903–905 (2018). https://doi.org/10.1038/s41594-018-0139-0

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