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Cell. 2017 May 4;169(4):679-692.e14. doi: 10.1016/j.cell.2017.04.021.

The RNA Exosome Syncs IAV-RNAPII Transcription to Promote Viral Ribogenesis and Infectivity.

Author information

1
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
2
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158-2140, USA.
3
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
4
Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
5
Regeneron Pharmaceuticals and Regeneron Genetics Center, Tarrytown, NY 10591, USA.
6
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
7
Department of Neurology, University of California, Los Angeles, CA 90095, USA.
8
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
9
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
10
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA. Electronic address: ivan.marazzi@mssm.edu.

Abstract

The nuclear RNA exosome is an essential multi-subunit complex that controls RNA homeostasis. Congenital mutations in RNA exosome genes are associated with neurodegenerative diseases. Little is known about the role of the RNA exosome in the cellular response to pathogens. Here, using NGS and human and mouse genetics, we show that influenza A virus (IAV) ribogenesis and growth are suppressed by impaired RNA exosome activity. Mechanistically, the nuclear RNA exosome coordinates the initial steps of viral transcription with RNAPII at host promoters. The viral polymerase complex co-opts the nuclear RNA exosome complex and cellular RNAs en route to 3' end degradation. Exosome deficiency uncouples chromatin targeting of the viral polymerase complex and the formation of cellular:viral RNA hybrids, which are essential RNA intermediates that license transcription of antisense genomic viral RNAs. Our results suggest that evolutionary arms races have shaped the cellular RNA quality control machinery.

KEYWORDS:

Influenza virus polymerase; RNA chimeras; RNA exosome; RNA hybrids; RNA surveillance; RNAPII elongation; epigenetics; host-pathogen interactions; neurodegeneration; non-coding RNA

PMID:
28475896
DOI:
10.1016/j.cell.2017.04.021
[Indexed for MEDLINE]
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