Influenza A Virus Utilizes Suboptimal Splicing to Coordinate the Timing of Infection

Mark A. Chua, Sonja Schmid, Jasmine T. Perez, Ryan A. Langlois, Benjamin R. tenOever

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Influenza A virus is unique as an RNA virus in that it replicates in the nucleus and undergoes splicing. With only ten major proteins, the virus must gain nuclear access, replicate, assemble progeny virions in the cytoplasm, and then egress. In an effort to elucidate the coordination of these events, we manipulated the transcript levels from the bicistronic nonstructural segment that encodes the spliced virus product responsible for genomic nuclear export. We find that utilization of an erroneous splice site ensures the slow accumulation of the viral nuclear export protein (NEP) while generating excessive levels of an antagonist that inhibits the cellular response to infection. Modulation of this simple transcriptional event results in improperly timed export and loss of virus infection. Together, these data demonstrate that coordination of the influenza A virus life cycle is set by a " molecular timer" that operates on the inefficient splicing of a virus transcript.

Original languageEnglish (US)
Pages (from-to)23-29
Number of pages7
JournalCell reports
Volume3
Issue number1
DOIs
StatePublished - Jan 31 2013

Bibliographical note

Funding Information:
This work is supported in part by the National Institutes of Health (grants A1093571 and A1080624 from the National Institute of Allergy and Infectious Diseases). J.T.P. and R.A.L. are supported by the Mount Sinai School of Medicine Hematopoietic T32 training grant (T32HL094283). B.R.t. is supported in part by the Pew Charitable Trust and the Burroughs Wellcome Fund. We would like to thank Peter Staeheli and Georg Kochs (University of Freiburg, Freiburg, Germany) for the Ifnar1 −/−/ Il28r −/− mice and for the Mx1 antibody, and Peter Palese (Mount Sinai School of Medicine, New York University) for the recombinant segment four used for VLV construction and the MDCK-HA cells required for VLV construction.

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