FUNCTIONAL INTERPLAY OF INFLUENZA A VIRUS NS1 AND PA-X PROTEINS MEDIATES HOST SHUTOFF

Abstract

Host shutoff is a mechanism to inhibit gene expression and limit the innate immune response. IAV produces two host shutoff proteins: PA-X and NS1. PA-X is an endonuclease that targets and cleaves host mRNAs. NS1 limits host pre-mRNA 3’-end processing, nuclear export, translation, and the innate immune response. PA-X and NS1 have important independent roles in host shutoff, but their functional relationship remains elusive. PA-X activity depletes cytoplasmic mRNAs, leading to a nuclear accumulation of cytoplasmic PABP. PA-X activity has also been linked to aberrant increases in nuclear poly adenylated (p(A)) RNAs. Recombinant IAV lacking functional NS1 had no nuclear accumulation of PABP during infection and there was evidence of decreased downregulation of PA-X targeted transcripts. Meanwhile, accumulation of p(A) RNAs during infection occurred independently of PA-X and NS1. These data suggest PA-X and NS1 have an important functional relationship and NS1 may enhance PA-X’s host shutoff activity during infection.