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Cell Rep. 2019 Apr 16;27(3):776-792.e7. doi: 10.1016/j.celrep.2019.03.063.

The Influenza A Virus Endoribonuclease PA-X Usurps Host mRNA Processing Machinery to Limit Host Gene Expression.

Author information

1
Graduate Program in Molecular Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA.
2
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada.
3
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA.
4
Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA; Computational Research Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
5
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada. Electronic address: craig.mccormick@dal.ca.
6
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada. Electronic address: d.khaperskyy@dal.ca.
7
Graduate Program in Molecular Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA. Electronic address: marta.gaglia@tufts.edu.

Abstract

Many viruses shut off host gene expression to inhibit antiviral responses. Viral proteins and host proteins required for viral replication are typically spared in this process, but the mechanisms of target selectivity during host shutoff remain poorly understood. Using transcriptome-wide and targeted reporter experiments, we demonstrate that the influenza A virus endoribonuclease PA-X usurps RNA splicing to selectively target host RNAs for destruction. Proximity-labeling proteomics reveals that PA-X interacts with cellular RNA processing proteins, some of which are partially required for host shutoff. Thus, PA-X taps into host nuclear pre-mRNA processing mechanisms to destroy nascent mRNAs shortly after their synthesis. This mechanism sets PA-X apart from other viral host shutoff proteins that target actively translating mRNAs in the cytoplasm. Our study reveals a unique mechanism of host shutoff that helps us understand how influenza viruses suppress host gene expression.

KEYWORDS:

CFIm; PA-X; host shutoff; influenza; splicing

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