The influenza A virus endoribonuclease PA-X usurps host mRNA processing machinery to limit host gene expression

Lea Gaucherand; Brittany K. Porter; Summer K. Schmaling; Christopher Harley Rycroft; Yuzo Kevorkian; Craig McCormick; Denys A. Khaperskyy; Marta Maria Gaglia

The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. . https://doi.org/10.1101/442996 doi: bioRxiv preprint substantially decreased by other regulatory mechanisms during infection, such that their targeting 177 by PA-X is masked. Interestingly, based on gene ontology (GO) term analysis, the host shutoff-178 resistant RNAs were significantly enriched for genes involved in transcription and translation, 179 including ribosomal RNA processing, ribosomal proteins, and membrane protein synthesis 180 ( Figure 3D ). This result is consistent with the IAV requirement for host biosynthetic machinery IAV infection, as demonstrated by their higher expression compared to all detected RNAs, their 189 levels were even higher in the absence of PA-X ( Figure 3E ). While only 12% of ISGs were up-190 regulated during wt IAV infection, and only 4% were induced more than two-fold, 35% of the 191 ISGs were up-regulated in IAV PA(ΔX)-infected cells, with 15% above two-fold. While the 192 activity of PA-X is clearly not limited to ISGs, these data indicate that PA-X contributes to 193 dampening the cell-intrinsic response to infection. 194