To gain preferential access to the protein synthesis machinery and to disrupt induction of antiviral responses by infected cell many viruses block host gene expression. This blockade is called host shutoff and it is mediated by viral factors that either destroy host messenger RNAs (mRNAs) or interfere with their synthesis.
Influenza A virus (IAV) encodes a host shutoff endonuclease PA-X, and our recent work in collaboration with the laboratory of Dr. Marta Gaglia at Tufts University (Boston, MA) revealed that PA-X cleaves cellular mRNAs but not the other types of host RNA (e.g. ribosomal RNA) or viral mRNAs.
A short 61 amino acid C-terminal region of PA-X, termed X-ORF, is highly conserved in mammalian and avian IAV strains and is necessary for PA-X shutoff activity. Our studies demonstrated that the X-ORF mediates nuclear accumulation of PA-X, and that PA-X can degrade both cytoplasmic and nuclear host mRNAs.
Our ongoing collaboration with Gaglia lab is aimed at understanding the specificity of PA-X and the role of X-ORF in RNA target selection.
Gaucherand L, Porter B, Levene R, Price E, Schmaling S, Rycroft C, Kevorkian Y, McCormick C, Khaperskyy D, Gaglia M. (2019) The Influenza A Virus Endoribonuclease PA-X Usurps Host mRNA Processing Machinery to Limit Host Gene Expression. Cell Rep. 27(3):776-792.e7
Khaperskyy, D.A., Schmaling, S., Larkins-Ford, J., McCormick, C., and Gaglia, M.M. (2016) Selective degradation of host RNA polymerase II transcripts by influenza A virus PA-X host shutoff protein. PLoS Pathog. 12: e1005427.
Khaperskyy, D.A. and McCormick, C. (2015) Timing Is Everything: Coordinated Control of Host Shutoff by Influenza A Virus NS1 and PA-X Proteins. J Virol. 89:6528-31.