The Influenza A Virus Endoribonuclease PA-X Usurps Host mRNA Processing Machinery to Limit Host Gene Expression
Lea Gaucherand,
Brittany K. Porter,
Rachel E. Levene,
Emma L. Price,
Summer K. Schmaling,
Chris H. Rycroft,
Yuzo Kevorkian,
Craig McCormick,
Denys A. Khaperskyy,
Marta M. Gaglia
Affiliations
Lea Gaucherand
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
Brittany K. Porter
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada
Rachel E. Levene
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
Emma L. Price
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada
Summer K. Schmaling
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA
Chris H. Rycroft
Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA; Computational Research Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Yuzo Kevorkian
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
Craig McCormick
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada; Corresponding author
Denys A. Khaperskyy
Department of Microbiology & Immunology, Dalhousie University, Halifax, NS, Canada; Corresponding author
Marta M. Gaglia
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; Corresponding author
Summary: 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. : Gaucherand et al. uncover a unique relationship between RNA degradation by the influenza A virus ribonuclease PA-X and host RNA splicing, which allows PA-X to selectively target host RNAs for destruction. Keywords: influenza, host shutoff, PA-X, splicing, CFIm
