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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • A549 Cells
  • Cleavage And Polyadenylation Specificity Factor / antagonists & inhibitors
  • Cleavage And Polyadenylation Specificity Factor / genetics
  • Cleavage And Polyadenylation Specificity Factor / metabolism
  • Down-Regulation
  • Endoribonucleases / metabolism
  • HEK293 Cells
  • Host-Pathogen Interactions
  • Humans
  • Influenza A virus / physiology*
  • Interferons / genetics
  • Interferons / metabolism
  • Mutagenesis, Site-Directed
  • RNA Interference
  • RNA Precursors / metabolism
  • RNA Splice Sites
  • RNA Splicing*
  • RNA, Messenger / metabolism*
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Up-Regulation
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism*
  • mRNA Cleavage and Polyadenylation Factors / antagonists & inhibitors
  • mRNA Cleavage and Polyadenylation Factors / genetics
  • mRNA Cleavage and Polyadenylation Factors / metabolism


  • Cleavage And Polyadenylation Specificity Factor
  • Nudt21 protein, human
  • PA-X protein, influenza A virus
  • RNA Precursors
  • RNA Splice Sites
  • RNA, Messenger
  • RNA, Small Interfering
  • Repressor Proteins
  • Viral Nonstructural Proteins
  • cleavage factor Im, human
  • interferon-lambda, human
  • mRNA Cleavage and Polyadenylation Factors
  • Interferons
  • Endoribonucleases