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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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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Frontiers of Biology in China (2007)