Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript (original) (raw)

Nature volume 442, pages 82–85 (2006)Cite this article

A Retraction to this article was published on 31 January 2008

Abstract

MicroRNAs (miRNAs) are a class of small RNA molecules that regulate the stability or the translational efficiency of target messenger RNAs (mRNAs)1,2. The latency-associated transcript (LAT) of herpes simplex virus-1 (HSV-1) is the only viral gene expressed during latent infection in neurons3. LAT inhibits apoptosis and maintains latency by promoting the survival of infected neurons4. No protein product has been attributed to the LAT gene and the mechanism by which LAT protects cells from apoptosis is not yet known. Here we show that a miRNA encoded by the HSV-1 LAT gene confers resistance to apoptosis. Neuroblastoma cells transfected with a fragment of the LAT gene show reduced susceptibility to cell death. The anti-apoptotic function of LAT has been mapped to a region within the first exon5,6. We have identified and characterized a microRNA (miR-LAT) generated from the exon 1 region of the HSV-1 LAT gene. The LAT miRNA was found to accumulate in cells transiently transfected with the LAT gene fragment or infected with a wild-type strain of HSV-1. A mutant virus in which a 372-nucleotide fragment encompassing the mature miRNA was deleted neither protected the infected cells from apoptosis nor generated an miRNA. miR-LAT exerts its anti-apoptotic effect by downregulation of transforming growth factor (TGF)-β 1 and SMAD3 expression, both of which are functionally linked in the TGF-β pathway. Our results suggest that the miRNA encoded by the HSV-1 LAT gene regulates the induction of apoptosis in infected cells by modulation of TGF-β signalling and thus contributes to the persistence of HSV in a latent form in sensory neurons.

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Acknowledgements

We thank K.-T. Jeang for the GFP-shRNA construct; Z. Mourelatos for the PRL-TK vector; and R. Sheikhattar for the Dicer polyclonal antibody. We thank B. Brunk for help with the computational analysis. We also thank T. Chendrimada for advice and help with miRNA protocols. We acknowledge S. Berges for critical review of the manuscript. This work was supported by a National Institute of Health grant. A.G.H. is supported by an NSF Career Award Grant. Author Contributions A.G. conceived the project and carried out all experiments described. J.J.G. provided technical assistance. P.S. and A.G.H. developed and applied computational algorithm for miRNA detection and target prediction. N.W.F. directed and supervised the experimental work and interpretation of data. The manuscript was prepared by A.G. and N.W.F.

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Authors and Affiliations

  1. Department of Microbiology, University of Pennsylvania School of Medicine,
    A. Gupta, J. J. Gartner & N. W. Fraser
  2. Department of Genetics and Penn Center for Bioinformatics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA
    P. Sethupathy & A. G. Hatzigeorgiou

Authors

  1. A. Gupta
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  2. J. J. Gartner
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  3. P. Sethupathy
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  4. A. G. Hatzigeorgiou
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  5. N. W. Fraser
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Correspondence toN. W. Fraser.

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Gupta, A., Gartner, J., Sethupathy, P. et al. Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript.Nature 442, 82–85 (2006). https://doi.org/10.1038/nature04836

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Editorial Summary

How herpes simplex hides

Herpes simplex virus 1 (HSV-1) can lie latent in the peripheral nervous system until reactivated by stress of some kind, when infectious viruses are again produced, forming familiar epithelial herpes infections such as cold sores. Just one viral gene is expressed during this latency phase, and no viral particles are produced. The product of that one gene has now been identified and the subtlety of the latency ploy is revealed: the virus produces a microRNA that protects the infected neurons from cell death (or apoptosis), so that the infection persists until reactivated. Mammalian cells are known to use the RNAi (RNA interference) pathway to restrict viral propagation but here the tables are turned to the benefit of the virus.

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