Giuseppe
Emeritus
Influenza A virus-generated small RNAs regulate the switch from transcription to replication (Proc Natl Acad Sci USA, abstract, edited)
[Source: PNAS, <cite cite="http://www.pnas.org/content/107/25/11525.short?rss=1">Influenza A virus-generated small RNAs regulate the switch from transcription to replication ? PNAS</cite>. Abstract, edited.]
Influenza A virus-generated small RNAs regulate the switch from transcription to replication
Jasmine T. Perez a,b, Andrew Varble a,b, Ravi Sachidanandam c, Ivan Zlatev d, Muthiah Manoharan d, Adolfo Garc?a-Sastre a,b,e,f, and Benjamin R. tenOever a,b,e,1
Author Affiliations
a) Microbiology Graduate School Training Program, Departments of b) Microbiology and c) Immunobiology, e) Global Health and Emerging Pathogens Institute, and f) Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029; and d) Department of Drug Discovery, Alnylam Pharmaceuticals, Cambridge, MA 02142
Edited* by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved May 7, 2010 (received for review February 17, 2010)
Abstract
The discovery of regulatory small RNAs continues to reshape paradigms in both molecular biology and virology. Here we describe examples of influenza A virus-derived small viral RNAs (svRNAs). svRNAs are 22?27 nt in length and correspond to the 5′ end of each of the viral genomic RNA (vRNA) segments. Expression of svRNA correlates with the accumulation of vRNA and a bias in RNA-dependent RNA polymerase (RdRp) activity from transcription toward genome replication. Synthesis of svRNA requires the RdRp, nucleoprotein and the nuclear export protein NS2. In addition, svRNA is detectable during replication of various influenza A virus subtypes across multiple host species and associates physically with the RdRp. We demonstrate that depletion of svRNA has a minimal impact on mRNA and complementary vRNA (cRNA) but results in a dramatic loss of vRNA in a segment-specific manner. We propose that svRNA triggers the viral switch from transcription to replication through interactions with the viral polymerase machinery. Taken together, the discovery of svRNA redefines the mechanistic switch of influenza virus transcription/replication and provides a potential target for broad-range, anti-influenza virus-based therapeutics.
* microRNA * replicase * replication switch * RNA dependent RNA polymerase * transcriptase
Footnotes
1) To whom correspondence should be addressed. E-mail: Benjamin.tenOever@mssm.edu.
Author contributions: J.T.P., A.G.-S., and B.R.t. designed research; J.T.P. and A.V. performed research; I.Z., M.M., and A.G.-S. contributed new reagents/analytic tools; J.T.P., R.S., and B.R.t. analyzed data; and J.T.P. and B.R.t. wrote the paper.
The authors declare no conflict of interest.
This Direct Submission article had a prearranged editor.
See Commentary on page 11153.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1001984107/-/DCSupplemental.
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[Source: PNAS, <cite cite="http://www.pnas.org/content/107/25/11525.short?rss=1">Influenza A virus-generated small RNAs regulate the switch from transcription to replication ? PNAS</cite>. Abstract, edited.]
Influenza A virus-generated small RNAs regulate the switch from transcription to replication
Jasmine T. Perez a,b, Andrew Varble a,b, Ravi Sachidanandam c, Ivan Zlatev d, Muthiah Manoharan d, Adolfo Garc?a-Sastre a,b,e,f, and Benjamin R. tenOever a,b,e,1
Author Affiliations
a) Microbiology Graduate School Training Program, Departments of b) Microbiology and c) Immunobiology, e) Global Health and Emerging Pathogens Institute, and f) Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, NY 10029; and d) Department of Drug Discovery, Alnylam Pharmaceuticals, Cambridge, MA 02142
Edited* by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved May 7, 2010 (received for review February 17, 2010)
Abstract
The discovery of regulatory small RNAs continues to reshape paradigms in both molecular biology and virology. Here we describe examples of influenza A virus-derived small viral RNAs (svRNAs). svRNAs are 22?27 nt in length and correspond to the 5′ end of each of the viral genomic RNA (vRNA) segments. Expression of svRNA correlates with the accumulation of vRNA and a bias in RNA-dependent RNA polymerase (RdRp) activity from transcription toward genome replication. Synthesis of svRNA requires the RdRp, nucleoprotein and the nuclear export protein NS2. In addition, svRNA is detectable during replication of various influenza A virus subtypes across multiple host species and associates physically with the RdRp. We demonstrate that depletion of svRNA has a minimal impact on mRNA and complementary vRNA (cRNA) but results in a dramatic loss of vRNA in a segment-specific manner. We propose that svRNA triggers the viral switch from transcription to replication through interactions with the viral polymerase machinery. Taken together, the discovery of svRNA redefines the mechanistic switch of influenza virus transcription/replication and provides a potential target for broad-range, anti-influenza virus-based therapeutics.
* microRNA * replicase * replication switch * RNA dependent RNA polymerase * transcriptase
Footnotes
1) To whom correspondence should be addressed. E-mail: Benjamin.tenOever@mssm.edu.
Author contributions: J.T.P., A.G.-S., and B.R.t. designed research; J.T.P. and A.V. performed research; I.Z., M.M., and A.G.-S. contributed new reagents/analytic tools; J.T.P., R.S., and B.R.t. analyzed data; and J.T.P. and B.R.t. wrote the paper.
The authors declare no conflict of interest.
This Direct Submission article had a prearranged editor.
See Commentary on page 11153.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1001984107/-/DCSupplemental.
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