Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript (original) (raw)
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- Published: 31 May 2006
Nature volume 442, pages 82–85 (2006)Cite this article
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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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References
- Ambros, V. MicroRNAs: tiny regulators with great potential. Cell 107, 823–826 (2001)
Article CAS PubMed Google Scholar - Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism and function. Cell 116, 281–297 (2004)
Article CAS PubMed Google Scholar - Jones, C. Herpes simplex virus type 1 and bovine herpesvirus 1 latency. Clin. Microbiol. Rev. 16, 79–95 (2003)
Article CAS PubMed PubMed Central Google Scholar - Perng, G. C. et al. Virus-induced neuronal apoptosis blocked by the herpes simplex virus latency-associated transcript. Science 287, 1500–1503 (2000)
Article ADS CAS PubMed Google Scholar - Ahmed, M., Lock, M., Miller, C. G. & Fraser, N. W. Regions of the herpes simplex virus type 1 latency-associated transcript that protect cells from apoptosis in vitro and protect neuronal cells in vivo. J. Virol. 76, 717–729 (2002)
Article CAS PubMed PubMed Central Google Scholar - Inman, M. et al. Region of herpes simplex virus type 1 latency-associated transcript sufficient for wild-type spontaneous reactivation promotes cell survival in tissue culture. J. Virol. 75, 3636–3646 (2001)
Article CAS PubMed PubMed Central Google Scholar - Bennasser, Y., Le, S. Y., Benkirane, M. & Jeang, K. T. Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing. Immunity 22, 607–619 (2005)
Article CAS PubMed Google Scholar - Laferriere, A., Gautheret, D. & Cedergren, R. An RNA pattern matching program with enhanced performance and portability. Comput. Appl. Biosci. 10, 211–212 (1994)
CAS PubMed Google Scholar - Zuker, M. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res. 31, 3406–3415 (2003)
Article CAS PubMed PubMed Central Google Scholar - Tomari, Y. & Zamore, P. D. Perspective: machines for RNAi. Genes Dev. 19, 517–529 (2005)
Article CAS PubMed Google Scholar - John, B. et al. Human MicroRNA targets. PLoS Biol. 2, e363 (2004)
Article PubMed PubMed Central Google Scholar - Derynck, R., Akhurst, R. J. & Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nature Genet. 29, 117–129 (2001)
Article CAS PubMed Google Scholar - Feng, X. H. & Derynck, R. Specificity and versatility in TGF-β signaling through Smads. Annu. Rev. Cell Dev. Biol. 21, 659–693 (2005)
Article CAS PubMed Google Scholar - Schuster, N. & Krieglstein, K. Mechanisms of TGF-β-mediated apoptosis. Cell Tissue Res. 307, 1–14 (2002)
Article CAS PubMed Google Scholar - Zawel, L. et al. Human Smad3 and Smad4 are sequence-specific transcription activators. Mol. Cell 1, 611–617 (1998)
Article CAS PubMed Google Scholar - Jin, L. et al. Identification of herpes simplex virus type 1 latency-associated transcript sequences that both inhibit apoptosis and enhance the spontaneous reactivation phenotype. J. Virol. 77, 6556–6561 (2003)
Article CAS PubMed PubMed Central Google Scholar - Jin, L. et al. A herpes simplex virus type 1 mutant expressing a baculovirus inhibitor of apoptosis gene in place of latency-associated transcript has a wild-type reactivation phenotype in the mouse. J. Virol. 79, 12286–12295 (2005)
Article CAS PubMed PubMed Central Google Scholar - Sullivan, C. S. & Ganem, D. MicroRNAs and viral infection. Mol. Cell 20, 3–7 (2005)
Article CAS PubMed Google Scholar - Schutz, S. & Sarnow, P. Interaction of viruses with the mammalian RNA interference pathway. Virology 344, 151–157 (2006)
Article PubMed Google Scholar - Chendrimada, T. P. et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436, 740–744 (2005)
Article ADS CAS PubMed PubMed Central Google Scholar - Lau, N. C., Lim, L. P., Weinstein, E. G. & Bartel, D. P. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294, 797–799 (2001)
Article Google Scholar - Pfeffer, S., Lagos-Quintana, M. & Tuschl, T. in Current Protocols in Molecular Biology (eds Ausbel, F. M. et al.) 26.4.1–26.4.18 (Wiley Interscience, New York, 2003)
Google Scholar
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
- Department of Microbiology, University of Pennsylvania School of Medicine,
A. Gupta, J. J. Gartner & N. W. Fraser - Department of Genetics and Penn Center for Bioinformatics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA
P. Sethupathy & A. G. Hatzigeorgiou
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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
- Received: 27 March 2006
- Accepted: 25 April 2006
- Published: 31 May 2006
- Issue Date: 06 July 2006
- DOI: 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.